Drug delivery medical device

ABSTRACT

A medical device that releases a pharmaceutical agent to a target site is disclosed. The medical device includes a balloon, and a coating on at least a portion of the balloon. The coating includes particles of a pharmaceutical agent. Each particle of the particles of the pharmaceutical agent is at least partially encapsulated in a polymer material. A method of releasing a pharmaceutical agent at a target site is also disclosed. The method includes the steps of providing a device including a balloon, and a coating on at least a portion of the balloon, the coating including particles of a pharmaceutical agent, and each particle of the pharmaceutical agent is at least partially encapsulated in a polymer material; positioning the device to allow the balloon to reach the target site; and inflating the balloon of the device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.61/715,768, filed Oct. 18, 2012; and relates to PCT Application No.PCT/US2012/060896 filed Oct. 18, 2012, U.S. Provisional Application No.61/548,650 filed Oct. 18, 2011, U.S. Provisional Application No.61/581,544 filed Dec. 29, 2011, and PCT Application No.PCT/US2012/046545 filed on Jul. 12, 2012 the contents of each of whichare incorporated herein in their entirety.

BACKGROUND OF THE INVENTION

There is a need for medical device technology that can rapidly,efficiently, reproducibly and safely transfer a Drug DeliveryFormulation from the surface of a percutaneous medical device (acoating) onto/into a specific site in the body.

SUMMARY OF THE INVENTION

Provided herein is a medical device comprising a balloon, and a coatingon at least a portion of the balloon, wherein the coating comprisesparticles of a pharmaceutical agent, and wherein each particle of thepharmaceutical agent are at least partially encapsulated in a polymermaterial.

In one embodiment, at least 50% of the surface area of thepharmaceutical agent is encapsulated in the polymer material. In anotherembodiment, at least 75% of the surface area of the pharmaceutical agentis encapsulated in the polymer material. In another embodiment, at least90% of the surface area of the pharmaceutical agent is encapsulated inthe polymer material. In another embodiment, at least 95% of the surfacearea of the pharmaceutical agent is encapsulated in the polymermaterial.

In one embodiment, the polymer layer has an average thickness of from 2microns to 20 microns. In another embodiment, the polymer layer has anaverage thickness of from 5 microns to 15 microns. In anotherembodiment, the polymer layer has an average thickness of about 10microns.

In one embodiment, the pharmaceutical agent has a crystallinity of atleast 5%. In another embodiment, the pharmaceutical agent has acrystallinity of at least 20%. In another embodiment, the pharmaceuticalagent has a crystallinity of from 25% to 95%.

In one embodiment, an average particle size of the encapsulatedpharmaceutical agent is from 5 nm to 150 nm. In a further refinement, anaverage particle size of the pharmaceutical agent is from 10 nm to 100nm. In another embodiment, an average particle size of the encapsulatedpharmaceutical agent is from 1 micron to 50 micron. In anotherembodiment, an average particle size of the encapsulated pharmaceuticalagent is from 1 micron to 20 micron. In another embodiment, an averageparticle size of the encapsulated pharmaceutical agent is from 1 micronto 10 micron. In a refinement, an average particle size of theencapsulated pharmaceutical agent is from 1 micron to 5 micron.

In one embodiment, a weight ratio between the pharmaceutical agent andthe polymer material is from 1:99 to 70:30. In another embodiment, aweight ratio between the pharmaceutical agent and the polymer materialis from 25:75 to 40:60. In another embodiment, a weight ratio of thepharmaceutical agent and the polymer material is from 40:60 to 60:40.

In one embodiment, the pharmaceutical agent is at least partiallyencapsulated in the polymer layer by spray-drying a mixture of thepharmaceutical agent, the polymer, and a solvent. In a refinement, themixture is a solution and the solvent is a polar aprotic solvent. In afurther refinement, the polar aprotic solvent is selected fromtetrahydrofuran, acetonitrile, and mixtures thereof. In anotherrefinement, the mixture is a slurry and the solvent is water.

In one embodiment, the pharmaceutical agent is at least partiallyencapsulated in the polymer material by spraying and drying a solutionof the bioabsorbable polymer on the particles of the pharmaceuticalagent. In a refinement, the solution comprises the polymer and a polaraprotic solvent. In a further refinement, the polar aprotic solvent isselected from tetrahydrofuran, acetonitrile, and mixtures thereof.

In one embodiment, the pharmaceutical agent is at least partiallyencapsulated in the polymer material by adding particles of the polymerto the pharmaceutical agent in a tumbling vessel. In a refinement, theparticles of the polymer have an average particle size of from 10microns to 100 microns. In another refinement, the particles of thepolymer are added at a rate of from 100 μg to 1000 μg per minute. Inanother refinement, the particles of the polymer are added at a rate offrom 300 μg to 500 μg per minute.

In one embodiment, the pharmaceutical agent is at least partiallyencapsulated in the polymer layer by forming an emulsion-based mixturecomprising the pharmaceutical agent and the polymer material, andseparating the polymer-encapsulated pharmaceutical agent from theemulsion-based mixture. In a refinement, the polymer material is amixture of PVA or PLGA. In further refinement, the PLGA has a weightratio from about 40:60 to about 60:40 lactic acid:glycolic acid. Inanother refinement, the pharmaceutical agent is amorphous.

In a further refinement the pharmaceutical agent is at least partiallyencapsulated in the polymer material by forming an emulsion-basedmixture comprising the pharmaceutical agent and the polymer material,evaporating a portion of the emulsion, and filtering the remainingemulsion. In a further refinement, the encapsulated pharmaceutical agentis resuspended and lyophilized. In another refinement, theemulsion-based mixture is formed by combining a first polymer solution,a second polymer solution, a third polymer solution, and apharmaceutical agent solution. In a further refinement, the first andthird polymer solutions comprise a first polymer and water. In a furtherrefinement, the first polymer is PVA. In a further refinement, the firstpolymer solution has a polymer concentration of from about 1% to about5%. In another refinement, the third polymer solution has a polymerconcentration of from about 0.5% to about 2%. In another refinement thesecond polymer solution is comprised of a second polymer and an organicsolvent. In a further refinement the second polymer is PLGA. In anotherrefinement the organic solvent is dochloromethane. In another refinementthe pharmaceutical agent solution comprises the pharmaceutical agent anda polar aprotic solvent. In a further refinement the aprotic solvent isdimethylsulfoxide. In another refinement, the emulsion is formed bymixing the pharmaceutical agent solution and the second polymersolution, adding the first polymer solution to that mixture,homogenizing the mixture, and adding the third polymer solution.

In another refinement the pharmaceutical agent is crystalline. In afurther embodiment the pharmaceutical agent is at least partiallyencapsulated in the polymer material by forming an emulsion-basedmixture comprising the pharmaceutical agent and at least one polymer andfiltering the emulsion. In a further refinement the encapsulatedpharmaceutical agent is resuspended and lyophilized. In anotherrefinement the emulsion-based mixture is formed by combining a firstpolymer solution, a second polymer solution, a third polymer solution,and the crystalline pharmaceutical agent. In a further refinement thefirst polymer solution comprises a first polymer and an organic solvent.In a further refinement the first polymer solution is combined with thesecond polymer solution and the organic solvent is allowed to evaporate.In a further refinement, the first polymer is PLGA. In anotherrefinement the organic solvent is dichloromethane. In anotherrefinement, the second and third polymer solutions comprise a secondpolymer and water. In a further refinement the second polymer is PVA. Ina further refinement the second polymer solution has a polymerconcentration of from about 0.5% to about 2%. In another refinement, thethird polymer solution has a polymer concentration of from about 1% toabout 5%. In another refinement the emulsion is formed by mixing thefirst polymer solution and the secdon polymer solution to form anemulsion, mixing the pharmaceutical agent and the third polymer solutionto form a suspension, and combining the emulsion and suspension.

In one embodiment, the pharmaceutical agent is a macrolideimmunosuppressant. In a refinement, the macrolide immunosuppressant israpamycin or a derivative, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative or an analog thereof. In another refinement, themacrolide immunosuppressant is selected from the group consisting ofrapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin. In anotherrefinement, the pharmaceutical agent is rapamycin.

In one embodiment, the polymer material comprises a bioabsorbablepolymer. In a refinement, the bioabsorbable polymer is selected from thegroup consisting of polylactides (PLA); poly(lactide-co-glycolide)(PLGA); polyanhydrides; polyorthoesters; poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA);polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),polyarginine, polyvinyl alcohol (PVA), and mixtures or co-polymersthereof. In another refinement, the bioabsorbable polymer is PLGA, PVA,polyarginine, or mixtures thereof. In a further refinement, thebioabsorbable polymer is a mixture of PLGA and PVA.

In one embodiment, the polymer layer comprises PLGA. In a refinement,the polymer layer is made of PLGA. In another embodiment, the polymerlayer comprises polyarginine. In a refinement, the polymer layer is madeof polyarginine. In a refinement, the PLGA comprises about 50:50 lacticacid:glycolic acid. In another embodiment, the polymer layer comprises adurable polymer.

In one embodiment, the medical device further comprises a binding agentdeposited on an exterior surface of the encapsulated particles of thepharmaceutical agent. In a refinement, a weight ratio between thebinding agent and the polymer is from 1:99 to 25:75. In anotherrefinement, a weight ratio between the binding agent and the polymer isfrom 1:99 to 10:90.

In one embodiment, the binding agent is deposited by spraying and dryinga solution of the binging agent on the encapsulated particles of thepharmaceutical agent. In a refinement, the solution comprises thebinding agent and water.

In one embodiment, the binding agent comprises at least one of:Polyarginine, Polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethylcellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI(Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB(Dimethylditetradecylammonium bromide). In a refinement, the bindingagent is Polyarginine. In a further refinement, the Polyarginine has anaverage molecular weight of about 70 kDa. In another refinement, thePolyarginine has an average molecular weight of 5-15 kDa.

In one embodiment, the encapsulated particles of the pharmaceuticalagent are deposited on the balloon using an eSTAT coating process.

In one embodiment, the medical device releases at least 3% of thepharmaceutical agent upon inflation of the balloon. In anotherembodiment, the medical device releases at least 5% or at least 10% ofthe pharmaceutical agent upon inflation of the balloon. In anotherembodiment, the medical device releases at least about 2 ng/mg, at leastabout 3 ng/mg, at least about 5 ng/mg, at least about 10 ng/mg, at leastabout 20 ng/mg, at least about 30 ng/mg, or at least about 40 ng/mg ofthe pharmaceutical agent 72 hours after inflation of the balloon.

In one embodiment, the balloon is an invertable balloon having anabluminal side; wherein the coating is provided on the abluminal side ofthe invertable balloon. In a refinement, the balloon is inverted withina catheter. In a further refinement, the balloon is capable of beingpushed out of the catheter using balloon inflation pressure or by movingthe distal end of the balloon distally through the balloon, or acombination thereof. In another refinement, the invertible balloon isinverted on an outside of a catheter. In a further refinement, atreatment length of the invertible balloon is controlled by partiallyun-inverting the invertible balloon on the outside of the catheter. Inanother further refinement, the medical device further comprises asheath provided over the invertible balloon. In another furtherrefinement, the sheath is retractable once the coated balloon reachesthe treatment site, is positioned near the treatment site, is positionedat the treatment site, is proximal to the treatment site, is distal tothe treatment site, or is within the treatment site.

In one embodiment, the medical device further comprises an occluderconfigured to block the flow of bodily fluids toward the balloon beforethe balloon is inflated. In a refinement, the occluder comprises asecond balloon. In another refinement, the balloon comprises first andsecond sections, the first section comprising the occluder and thesecond section comprising the coating. In another refinement, theballoon comprises a distal node and a proximal node wherein the distalnode comprises the coating and wherein the proximal node comprises theoccluder, or wherein the proximal node comprises the coating and whereinthe distal node comprises the occluder. In still another refinement, adistal portion of the balloon is coated and wherein a proximal portionof the balloon is not coated, and wherein the proximal portion of theballoon is the occlude, or wherein a proximal portion of the balloon iscoated and wherein a distal portion of the balloon is not coated, andwherein the distal portion of the balloon is the occluder.

Also provided herein is a method of releasing a pharmaceutical agent ata target site, comprising providing a device comprising a balloon, and acoating on at least a portion of the balloon, wherein the coatingcomprises particles of a pharmaceutical agent, and wherein each particleof the pharmaceutical agent is at least partially encapsulated in apolymer material; positioning the device to allow the balloon to reachthe target site; and inflating the balloon of the device, wherein atleast some of the pharmaceutical agent is released to the target siteupon inflating the balloon.

In one embodiment, the target site is a blood vessel, such as an artery.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference. This applicationrelates to U.S. Provisional Application No. 61/081,691, filed Jul. 17,2008, U.S. Provisional Application No. 61/226,239 filed Jul. 16, 2009,U.S. Provisional Application No. 61/212,964, filed Apr. 17, 2009, U.S.application Ser. No. 12/504,597, filed Jul. 16, 2009, U.S. applicationSer. No. 12/729,580, filed Mar. 23, 2010, PCT Application No.PCT/US2009/050883, filed Jul. 16, 2009, PCT Application No.PCT/US2010/028253, filed Mar. 23, 2010, and PCT Application No.PCT/US2010/042355, filed Jul. 16, 2010. The contents of theseapplications are incorporated herein by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 indicates the Average percent Sirolimus Eluted from the balloonsat various time points for Formulations F3, F5, and F7;

FIG. 2 depicts an example eSTAT process for coating 12 angioplastyballoons with sirolimus;

FIG. 3 depicts coating balloons according to an RESS process;

FIG. 4 depicts a method of preparing a coating formulation according toan embodiment herein.

FIG. 5 is an SEM image of microparticles of encapsulated rapamycinaccording to one embodiment herein; and

FIG. 6 is an SEM image of microparticles of encapsulated rapamycinaccording to another embodiment herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent ways in which the invention may be implemented, or all thefeatures that may be added to the instant invention. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. In addition,numerous variations and additions to the various embodiments suggestedherein will be apparent to those skilled in the art in light of theinstant disclosure, which do not depart from the instant invention.Hence, the following specification is intended to illustrate someparticular embodiments of the invention, and not to exhaustively specifyall permutations, combinations and variations thereof.

DEFINITIONS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

“Substrate” as used herein, refers to any surface upon which it isdesirable to deposit a coating. Biomedical implants are of particularinterest for the present invention; however the present invention is notintended to be restricted to this class of substrates. Those of skill inthe art will appreciate alternate substrates that could benefit from thecoating process described herein, such as pharmaceutical tablet cores,as part of an assay apparatus or as components in a diagnostic kit (e.g.a test strip). Examples of substrates that can be coated using themethods of the invention include surgery devices or medical devices,e.g., a catheter, a balloon, a cutting balloon, a wire guide, a cannula,tooling, an orthopedic device, a structural implant, stent, stent-graft,graft, vena cava filter, a heart valve, cerebrospinal fluid shunts,pacemaker electrodes, axius coronary shunts, endocardial leads, anartificial heart, and the like.

“Biomedical implant” as used herein refers to any implant for insertioninto the body of a human or animal subject, including but not limited tostents (e.g., coronary stents, vascular stents including peripheralstents and graft stents, urinary tract stents, urethral/prostaticstents, rectal stent, oesophageal stent, biliary stent, pancreaticstent), electrodes, catheters, leads, implantable pacemaker,cardioverter or defibrillator housings, joints, screws, rods, ophthalmicimplants, femoral pins, bone plates, grafts, anastomotic devices,perivascular wraps, sutures, staples, shunts for hydrocephalus, dialysisgrafts, colostomy bag attachment devices, ear drainage tubes, leads forpace makers and implantable cardioverters and defibrillators, vertebraldisks, bone pins, suture anchors, hemostatic barriers, clamps, screws,plates, clips, vascular implants, tissue adhesives and sealants, tissuescaffolds, various types of dressings (e.g., wound dressings), bonesubstitutes, intraluminal devices, vascular supports, etc.

The implants may be formed from any suitable material, including but notlimited to polymers (including stable or inert polymers, organicpolymers, organic-inorganic copolymers, inorganic polymers, andbiodegradable polymers), metals, metal alloys, inorganic materials suchas silicon, and composites thereof, including layered structures with acore of one material and one or more coatings of a different material.Substrates made of a conducting material facilitate electrostaticcapture. However, the invention contemplates the use of electrostaticcapture, as described herein, in conjunction with substrate having lowconductivity or which are non-conductive. To enhance electrostaticcapture when a non-conductive substrate is employed, the substrate isprocessed for example while maintaining a strong electrical field in thevicinity of the substrate. In some embodiments, however, noelectrostatic capture is employed in applying a coating to thesubstrate. In some embodiments of the methods and/or devices providedherein, the substrate is not charged in the coating process. In someembodiments of the methods and/or devices provided herein, an electricalpotential is not created between the substrate and the coatingapparatus.

Subjects into which biomedical implants of the invention may be appliedor inserted include both human subjects (including male and femalesubjects and infant, juvenile, adolescent, adult and geriatric subjects)as well as animal subjects (including but not limited to pig, rabbit,mouse, dog, cat, horse, monkey, etc.) for veterinary purposes and/ormedical research.

As used herein, a biological implant may include a medical device thatis not permanently implanted. A biological implant in some embodimentsmay comprise a device which is used in a subject on a transient basis.For non-limiting example, the biomedical implant may be a balloon, whichis used transiently to dilate a lumen and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In some embodiments, the biological implant may betemporarily implanted for a limited time, such as during a portion of amedical procedure, or for only a limited time (some time less thanpermanently implanted), or may be transiently implanted and/ormomentarily placed in the subject. In some embodiments, the biologicalimplant is not implanted at all, rather it is merely inserted into asubject during a medical procedure, and subsequently removed from thesubject prior to or at the time the medical procedure is completed. Insome embodiments, the biological implant is not permanently implantedsince it completely resorbs into the subject (i.e. is completelyresorbed by the subject). In a preferred embodiment the biomedicalimplant is an expandable balloon that can be expanded within a lumen(naturally occurring or non-naturally occurring) having a coatingthereon that is freed (at least in part) from the balloon and leftbehind in the lumen when the balloon is removed from the lumen.

Examples of pharmaceutical agents employed in conjunction with theinvention include, rapamycin, 40-O-(2-Hydroxyethyl)rapamycin(everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus). The active agent in some embodiments of the devices,coatings and/or methods provided herein comprises a macrolideimmunosuppressive drug. In some embodiments the macrolideimmunosuppressive drug comprises one or more of rapamycin,40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus). The active agent may be selected from a macrolideimmunosuppressive drug, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative, and an analog thereof. The active agent may beselected from sirolimus, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative, and an analog thereof.

The pharmaceutical agents may, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives (meaning saltswhich retain the biological effectiveness and properties of thecompounds of this invention and which are not biologically or otherwiseundesirable), and in the case of chiral active ingredients it ispossible to employ both optically active isomers and racemates ormixtures of diastereoisomers. As well, the pharmaceutical agent mayinclude at least one of: a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative, and an analog thereof.

The pharmaceutical agent may be an antibiotic agent, as describedherein.

In some embodiments of the methods, coatings, and/or devices providedherein, the size of the active agent in the coating is controlled. Insome embodiments, the active agent is sirolimus and wherein thesirolimus has an average size (mean diameter) of at least one of: 1.5μm, 2.5 μm, 645 nm, 100-200 nm, another controlled size, or acombination thereof. In some embodiments, the active agent is sirolimusand wherein the sirolimus has a median size of at least one of: 1.5 μm,2.5 μm, 645 nm, 100-200 nm, another controlled size, or a combinationthereof. In some embodiments, the active agent is sirolimus and whereinthe sirolimus has an average size (mean diameter) of at least one of:about 1.5 μm, about 2.5 μm, about 645 nm, about 100-200 nm, anothercontrolled size, or a combination thereof. In some embodiments, theactive agent is sirolimus and wherein the sirolimus has a median size ofat least one of: about 1.5 μm, about 2.5 μm, about 645 nm, about 100-200nm, another controlled size, or a combination thereof. In someembodiments, the active agent is sirolimus and wherein sirolimus atleast 75% of the sirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm, oranother controlled size. In some embodiments, the active agent issirolimus and wherein sirolimus at least 50% of the sirolimus as is 1.5μm, 2.5 μm, 645 nm, 100-200 nm, or another controlled size. In someembodiments, the active agent is sirolimus and wherein sirolimus atleast 90% of the sirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm, oranother controlled size.

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 50% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 75% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 90%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 95% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 97% crystalline. In some embodiments ofthe methods and/or devices provided herein pharmaceutical agent is atleast 98% crystalline. In some embodiments of the methods and/or devicesprovided herein the pharmaceutical agent is at least 99% crystalline.

“Prodrugs” are derivative compounds derivatized by the addition of agroup that endows greater solubility to the compound desired to bedelivered. Once in the body, the prodrug is typically acted upon by anenzyme, e.g., an esterase, amidase, or phosphatase, to generate theactive compound.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.There are many chemotherapeutic agents available in commercial use, inclinical evaluation and in pre-clinical development that are useful inthe devices and methods of the present invention for treatment ofcancers.

“Stability” as used herein in refers to the stability of the drug in acoating deposited on a substrate in its final product form (e.g.,stability of the drug in a coated stent). The term “stability” and/or“stable” in some embodiments is defined by 5% or less degradation of thedrug in the final product form. The term stability in some embodimentsis defined by 3% or less degradation of the drug in the final productform. The term stability in some embodiments is defined by 2% or lessdegradation of the drug in the final product form. The term stability insome embodiments is defined by 1% or less degradation of the drug in thefinal product form.

In some embodiments, the pharmaceutical agent is at least one of: 50%crystalline, 75% crystalline, 80% crystalline, 90% crystalline, 95%crystalline, 97% crystalline, and 99% crystalline followingsterilization of the device. In some embodiments, the pharmaceuticalagent crystallinity is stable wherein the crystallinity of thepharmaceutical agent following sterilization is compared to thecrystallinity of the pharmaceutical agent at least one of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In some embodiments, the pharmaceutical agentcrystallinity is stable wherein the crystallinity of the pharmaceuticalagent prior to sterilization is compared to the crystallinity of thepharmaceutical agent at least one of: 1 week after sterilization, 2weeks after sterilization, 4 weeks after sterilization, 1 month aftersterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In such embodiments, different devices may be tested fromthe same manufacturing lot to determine stability of the pharmaceuticalagent at the desired time points.

In some embodiments, the pharmaceutical agent crystallinity is stable atleast one of: 1 week after sterilization, 2 weeks after sterilization, 4weeks after sterilization, 1 month after sterilization, 2 months aftersterilization, 45 days after sterilization, 60 days after sterilization,90 days after sterilization, 3 months after sterilization, 4 monthsafter sterilization, 6 months after sterilization, 9 months aftersterilization, 12 months after sterilization, 18 months aftersterilization, and 2 years after sterilization.

In some embodiments, the pharmaceutical agent crystallinity on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity tested on a seconddevice manufactured from the same lot of devices and the same lot ofpharmaceutical agent at testing time point before sterilization (i.e.the crystallinity drops no more than from 99 to 94% crystalline, forexample, which is a 5% difference in crystallinity; the crystallinitydrops no more than from 99 to 95% crystalline, which is a 4% differencein crystallinity; the crystallinity drops no more than from 99 to 96%crystalline, for example, which is a 3% difference in crystallinity; thecrystallinity drops no more than from 99 to 97% crystalline, forexample, which is a 2% difference in crystallinity; the crystallinitydrops no more than from 99 to 98% crystalline, for example, which is a1% difference in crystallinity; in other examples, the startingcrystallinity percentage is one of 100%, 98%, 96%, 97%, 96%, 95%, 90%,85%, 80%, 75%, 70%, 60%, 50%, 30%, 25%, and/or anything in between).

In some embodiments, crystallinity of the pharmaceutical agent on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity of pharmaceuticalfrom the same lot of pharmaceutical agent tested at testing time pointbefore sterilization of the pharmaceutical agent.

In some embodiments, crystallinity of the pharmaceutical agent does notdrop more than 1%, 2%, 3%, 4%, and/or 5% between two testing time pointsafter sterilization neither of which time point being greater than 2years after sterilization. In some embodiments, crystallinity of thepharmaceutical agent does not drop more than 1%, 2%, 3%, 4%, and/or 5%between two testing time points after sterilization neither of whichtime point being greater than 5 years after sterilization. In someembodiments, two time points comprise two of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, 2 years aftersterilization, 3 years after sterilization, 4 years after sterilization,and 5 years after sterilization.

“Polymer” as used herein, refers to a series of repeating monomericunits that have been cross-linked or polymerized. Any suitable polymercan be used to carry out the present invention. It is possible that thepolymers of the invention may also comprise two, three, four or moredifferent polymers. In some embodiments of the invention only onepolymer is used. In certain embodiments a combination of two polymers isused. Combinations of polymers can be in varying ratios, to providecoatings with differing properties. Polymers useful in the devices andmethods of the present invention include, for example, stable or inertpolymers, organic polymers, organic-inorganic copolymers, inorganicpolymers, bioabsorbable, bioresorbable, resorbable, degradable, andbiodegradable polymers. Those of skill in the art of polymer chemistrywill be familiar with the different properties of polymeric compounds.

In some embodiments, the coating further comprises a polymer. In someembodiments, the active agent comprises a polymer. In some embodiments,the polymer comprises at least one of polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, polyurethanes,polyanhydrides, aliphatic polycarbonates, polyhydroxyalkanoates,silicone containing polymers, polyalkyl siloxanes, aliphatic polyesters,polyglycolides, polylactides, polylactide-co-glycolides,poly(e-caprolactone)s, polytetrahalooalkylenes, polystyrenes,poly(phosphasones), copolymers thereof, and combinations thereof.

In embodiments, the polymer is capable of becoming soft afterimplantation, for example, due to hydration, degradation or by acombination of hydration and degradation. In embodiments, the polymer isadapted to transfer, free, and/or dissociate from the substrate when atthe intervention site due to hydrolysis of the polymer. In variousembodiments, the device is coated with a bioabsorbable polymer that iscapable of resorbtion in at least one of: about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

Examples of polymers that may be used in the present invention include,but are not limited to polycarboxylic acids, cellulosic polymers,proteins, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers,polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans,polysaccharides, polyesters, aliphatic polyesters, polyurethanes,polystyrenes, copolymers, silicones, silicone containing polymers,polyalkyl siloxanes, polyorthoesters, polyanhydrides, copolymers ofvinyl monomers, polycarbonates, polyethylenes, polypropytenes,polylactic acids, polylactides, polyglycolic acids, polyglycolides,polylactide-co-glycolides, polycaprolactones, poly(e-caprolactone)s,polyhydroxybutyrate valerates, polyacrylamides, polyethers, polyurethanedispersions, polyacrylates, acrylic latex dispersions, polyacrylic acid,polyalkyl methacrylates, polyalkylene-co-vinyl acetates, polyalkylenes,aliphatic polycarbonates polyhydroxyalkanoates, polytetrahalooalkylenes,poly(phosphasones), polytetrahalooalkylenes, poly(phosphasones), andmixtures, combinations, and copolymers thereof.

The polymers of the present invention may be natural or synthetic inorigin, including gelatin, chitosan, dextrin, cyclodextrin,Poly(urethanes), Poly(siloxanes) or silicones, Poly(acrylates) such as[rho]oly(methyl methacrylate), poly(butyl methacrylate), andPoly(2-hydroxy ethyl methacrylate), Poly(vinyl alcohol)Poly(olefins)such as poly(ethylene), [rho]oly(isoprene), halogenated polymers such asPoly(tetrafluoroethylene)- and derivatives and copolymers such as thosecommonly sold as Teflon® products, Poly(vinylidine fluoride), Poly(vinylacetate), Poly(vinyl pyrrolidone), Poly(acrylic acid), Polyacrylamide,Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol), Poly(propyleneglycol), Poly(methacrylic acid); etc.

Suitable polymers also include absorbable and/or resorbable polymersincluding the following, combinations, copolymers and derivatives of thefollowing: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(l-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(l-lactide);PDO—poly(dioxanone); PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(l-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(l-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

In some embodiments of the devices, coatings and/or methods providedherein the polymer comprises PLGA. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises about 50:50Lactic acid:Glycolic acid. The PLGA may have at least one of: a MW ofabout 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDa to about 25KDa, and a MW of about 15 KDa to about 40 KDa. In some embodiments ofthe methods, coatings, or devices provided herein, the PLGA comprises50:50 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 40:60 to60:40 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 45:55 to55:45 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 48:52 to52:48 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 49:51 to51:49 Lactic acid:Glycolic acid. The use of the term “about” with regardto the ratio of Lactic acid to Glycolic acid in the PLGA, as usedherein, refers to ranges of ratios from 40:60 to 60:40, or from 45:55 to55:45, or from 48:52 to 52:48 or from 49:51 to 51:49, depending on theembodiment.

“Copolymer” as used herein refers to a polymer being composed of two ormore different monomers. A copolymer may also and/or alternatively referto random, block, graft, copolymers known to those of skill in the art.

“Biocompatible” as used herein, refers to any material that does notcause injury or death to the animal or induce an adverse reaction in ananimal when placed in intimate contact with the animal's tissues.Adverse reactions include for example inflammation, infection, fibrotictissue formation, cell death, or thrombosis. The terms “biocompatible”and “biocompatibility” when used herein are art-recognized and mean thatthe referent is neither itself toxic to a host (e.g., an animal orhuman), nor degrades (if it degrades) at a rate that produces byproducts(e.g., monomeric or oligomeric subunits or other byproducts) at toxicconcentrations, causes inflammation or irritation, or induces an immunereaction in the host. It is not necessary that any subject compositionhave a purity of 100% to be deemed biocompatible. Hence, a subjectcomposition may comprise 99%, 98%, 97%, 96%, 95%, 90% 85%, 80%, 75% oreven less of biocompatible agents, e.g., including polymers and othermaterials and excipients described herein, and still be biocompatible.“Non-biocompatible” as used herein, refers to any material that maycause injury or death to the animal or induce an adverse reaction in theanimal when placed in intimate contact with the animal's tissues. Suchadverse reactions are as noted above, for example.

The terms “bioabsorbable,” “biodegradable,” “bioerodible,”“bioresorbable,” and “resorbable” are art-recognized synonyms. Theseterms are used herein interchangeably. Bioabsorbable polymers typicallydiffer from non-bioabsorbable polymers in that the former may beabsorbed (e.g.; degraded) during use. In certain embodiments, such useinvolves in vivo use, such as in vivo therapy, and in other certainembodiments, such use involves in vitro use. In general, degradationattributable to biodegradability involves the degradation of abioabsorbable polymer into its component subunits, or digestion, e.g.,by a biochemical process, of the polymer into smaller, non-polymericsubunits. In certain embodiments, biodegradation may occur by enzymaticmediation, degradation in the presence of water (hydrolysis) and/orother chemical species in the body, or both. The bioabsorbability of apolymer may be indicated in-vitro as described herein or by methodsknown to one of skill in the art. An in-vitro test for bioabsorbabilityof a polymer does not require living cells or other biologic materialsto indicate bioabsorption properties (e.g. degradation, digestion).Thus, resorbtion, resorption, absorption, absorbtion, erosion may alsobe used synonymously with the terms “bioabsorbable,” “biodegradable,”“bioerodible,” and “bioresorbable.” Mechanisms of degradation of abioabsorbable polymer may include, but are not limited to, bulkdegradation, surface erosion, and combinations thereof.

As used herein, the term “biodegradation” encompasses both general typesof biodegradation. The degradation rate of a biodegradable polymer oftendepends in part on a variety of factors, including the chemical identityof the linkage responsible for any degradation, the molecular weight,crystallinity, biostability, and degree of cross-linking of suchpolymer, the physical characteristics (e.g., shape and size) of theimplant, and the mode and location of administration. For example, thegreater the molecular weight, the higher the degree of crystallinity,and/or the greater the biostability, the biodegradation of anybioabsorbable polymer is usually slower.

“Degradation” as used herein refers to the conversion or reduction of achemical compound to one less complex, e.g., by splitting off one ormore groups of atoms. Degradation of the coating may reduce thecoating's cohesive and adhesive binding to the device, therebyfacilitating transfer of the coating to the intervention site

As used herein, the term “durable polymer” refers to a polymer that isnot bioabsorbable (and/or is not bioerodable, and/or is notbiodegradable, and/or is not bioresorbable) and is, thus biostable. Insome embodiments, the device comprises a durable polymer. The polymermay include a cross-linked durable polymer. Example biocompatibledurable polymers include, but are not limited to: polyester, aliphaticpolyester, polyanhydride, polyethylene, polyorthoester, polyphosphazene,polyurethane, polycarbonate urethane, aliphatic polycarbonate, silicone,a silicone containing polymer, polyolefin, polyamide, polycaprolactam,polyamide, polyvinyl alcohol, acrylic polymer, acrylate, polystyrene,epoxy, polyethers, celluiosics, expanded polytetrafluoroethylene,phosphorylcholine, polyethyleneyerphthalate, polymethylmethavrylate,poly(ethylmethacrylate/n-butylmethacrylate), parylene C,polyethylene-co-vinyl acetate, polyalkyl methacrylates,polyalkylene-co-vinyl acetate, polyalkylene, polyalkyl siloxanes,polyhydroxyalkanoate, polyfluoroalkoxyphasphazine,poly(styrene-b-isobutylene-b-styrene), poly-butyl methacrylate,poly-byta-diene, and blends, combinations, homopolymers, condensationpolymers, alternating, block, dendritic, crosslinked, and copolymersthereof. The polymer may include a thermoset material. The polymer mayprovide strength for the coated implanable medical device. The polymermay provide durability for the coated implanable medical device. Thecoatings and coating methods provided herein provide substantialprotection from these by establishing a multi-layer coating which can bebioabsorbable or durable or a combination thereof, and which can bothdeliver active agents and provide elasticity and radial strength for thevessel in which it is delivered.

“Therapeutically desirable morphology” as used herein refers to thegross form and structure of the pharmaceutical agent, once deposited onthe substrate, so as to provide for optimal conditions of ex vivostorage, in vivo preservation and/or in vivo release. Such optimalconditions may include, but are not limited to increased shelf life(i.e., shelf stability), increased in vivo stability, goodbiocompatibility, good bioavailability or modified release rates.Typically, for the present invention, the desired morphology of apharmaceutical agent would be crystalline or semi-crystalline oramorphous, although this may vary widely depending on many factorsincluding, but not limited to, the nature of the pharmaceutical agent,the disease to be treated/prevented, the intended storage conditions forthe substrate prior to use or the location within the body of anybiomedical implant. Preferably at least 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%, and/or 100% of thepharmaceutical agent is in crystalline or semi-crystalline form.

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided hereinwherein the pharmaceutical agent is at least 50% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 75% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 95%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 97% crystalline. In someembodiments of the methods and/or devices provided herein pharmaceuticalagent is at least 98% crystalline. In some embodiments of the methodsand/or devices provided herein the pharmaceutical agent is at least 99%crystalline.

“Stabilizing agent” as used herein refers to any substance thatmaintains or enhances the stability of the biological agent. Ideallythese stabilizing agents are classified as Generally Regarded As Safe(GRAS) materials by the US Food and Drug Administration (FDA). Examplesof stabilizing agents include, but are not limited to carrier proteins,such as albumin, gelatin, metals or inorganic salts. Pharmaceuticallyacceptable excipient that may be present can further be found in therelevant literature, for example in the Handbook of PharmaceuticalAdditives: An International Guide to More Than 6000 Products by TradeName, Chemical, Function, and Manufacturer; Michael and Irene Ash(Eds.); Gower Publishing Ltd.; Aldershot, Hampshire, England, 1995.

“Intervention site” as used herein refers to the location in the bodywhere the coating is intended to be delivered (by transfer from, freeingfrom, and/or dissociating from the substrate). The intervention site canbe any substance in the medium surrounding the device, e.g., tissue,cartilage, a body fluid, etc. The intervention site can be the same asthe treatment site, i.e., the substance to which the coating isdelivered is the same tissue that requires treatment. Alternatively, theintervention site can be separate from the treatment site, requiringsubsequent diffusion or transport of the pharmaceutical or other agentaway from the intervention site.

“Compressed fluid” as used herein refers to a fluid of appreciabledensity (e.g., >0.2 g/cc) that is a gas at standard temperature andpressure. “Supercritical fluid,” “near-critical fluid,”“near-supercritical fluid,” “critical fluid,” “densified fluid,” or“densified gas,” as used herein refers to a compressed fluid underconditions wherein the temperature is at least 80% of the criticaltemperature of the fluid and the pressure is at least 50% of thecritical pressure of the fluid, and/or a density of +50% of the criticaldensity of the fluid.

Examples of substances that demonstrate supercritical or near criticalbehavior suitable for the present invention include, but are not limitedto carbon dioxide, isobutylene, ammonia, water, methanol, ethanol,ethane, propane, butane, pentane, dimethyl ether, xenon, sulfurhexafluoride, halogenated and partially halogenated materials such aschlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons,perfluorocarbons (such as perfluoromethane and perfluoropropane,chloroform, trichloro-fluoromethane, dichloro-difluoromethane,dichloro-tetrafluoroethane) and mixtures thereof. Preferably, thesupercritical fluid is hexafluoropropane (FC-236EA), or1,1,1,2,3,3-hexafluoropropane. Preferably, the supercritical fluid ishexafluoropropane (FC-236EA), or 1,1,1,2,3,3-hexafluoropropane for usein PLGA polymer coatings.

“Sintering” as used herein refers to the process by which parts of thepolymer or the entire polymer becomes continuous (e.g., formation of acontinuous polymer film). As discussed herein, the sintering process iscontrolled to produce a fully conformal continuous polymer (completesintering) or to produce regions or domains of continuous coating whileproducing voids (discontinuities) in the polymer. As well, the sinteringprocess is controlled such that some phase separation is obtained ormaintained between polymer different polymers (e.g., polymers A and B)and/or to produce phase separation between discrete polymer particles.Through the sintering process, the adhesions properties of the coatingare improved to reduce flaking of detachment of the coating from thesubstrate during manipulation in use. As described herein, in someembodiments, the sintering process is controlled to provide incompletesintering of the polymer. In embodiments involving incomplete sintering,a polymer is formed with continuous domains, and voids, gaps, cavities,pores, channels or, interstices that provide space for sequestering atherapeutic agent which is released under controlled conditions.Depending on the nature of the polymer, the size of polymer particlesand/or other polymer properties, a compressed gas, a densified gas, anear critical fluid or a super-critical fluid may be employed. In oneexample, carbon dioxide is used to treat a substrate that has beencoated with a polymer and a drug, using dry powder and RESSelectrostatic coating processes. In another example, isobutylene isemployed in the sintering process. In other examples a mixture of carbondioxide and isobutylene is employed. In another example,1,1,2,3,3-hexafluoropropane is employed in the sintering process.

When an amorphous material is heated to a temperature above its glasstransition temperature, or when a crystalline material is heated to atemperature above a phase transition temperature, the moleculescomprising the material are more mobile, which in turn means that theyare more active and thus more prone to reactions such as oxidation.However, when an amorphous material is maintained at a temperature belowits glass transition temperature, its molecules are substantiallyimmobilized and thus less prone to reactions. Likewise, when acrystalline material is maintained at a temperature below its phasetransition temperature, its molecules are substantially immobilized andthus less prone to reactions. Accordingly, processing drug components atmild conditions, such as the deposition and sintering conditionsdescribed herein, minimizes cross-reactions and degradation of the drugcomponent. One type of reaction that is minimized by the processes ofthe invention relates to the ability to avoid conventional solventswhich in turn minimizes -oxidation of drug, whether in amorphous,semi-crystalline, or crystalline form, by reducing exposure thereof tofree radicals, residual solvents, protic materials, polar-proticmaterials, oxidation initiators, and autoxidation initiators.

“Rapid Expansion of Supercritical Solutions” or “RESS” as used hereininvolves the dissolution of a polymer into a compressed fluid, typicallya supercritical fluid, followed by rapid expansion into a chamber atlower pressure, typically near atmospheric conditions. The rapidexpansion of the supercritical fluid solution through a small opening,with its accompanying decrease in density, reduces the dissolutioncapacity of the fluid and results in the nucleation and growth ofpolymer particles. The atmosphere of the chamber is maintained in anelectrically neutral state by maintaining an isolating “cloud” of gas inthe chamber. Carbon dioxide, nitrogen, argon, helium, or otherappropriate gas is employed to prevent electrical charge is transferredfrom the substrate to the surrounding environment.

“Electrostatic Rapid Expansion of Supercritical Solutions” or “e-RESS”or “eRESS” as used herein refers to Electrostatic Capture as describedherein combined with Rapid Expansion of Supercritical Solutions asdescribed herein. In some embodiments, Electrostatic Rapid Expansion ofSupercritical Solutions refers to Electrostatic capture as described inthe art, e.g., in U.S. Pat. No. 6,756,084, “Electrostatic deposition ofparticles generated from rapid expansion of supercritical fluidsolutions,” incorporated herein by reference in its entirety.

Electrostatic Capture may be used for depositing a coating on a device(e.g. a balloon), and may be referred to as “eSTAT” herein. Coating isapplied to the balloons via eSTAT attraction, where the positivelycharged coating coat a negatively charged device. For example, in someembodiments, sirolimus in crystalline form is applied to the balloonsvia eSTAT attraction where the positively charged drug particles coatthe negatively charged balloons. The sirolimus coated on the balloon, insome embodiments, has an inherently positive charge.

FIG. 2 depicts an example eSTAT process for coating 12 angioplastyballoons with sirolimus. In this example process, an eight literaluminum foil coated bell jar 2 is kept in place, but is notelectrically grounded. Milled sirolimus (15.5 mg) is placed in aSwagelok ½″ tee filter 18 (Swagelok, Inc., Supplemental Figure S15)connected to a pulsed pneumatic valve 20 (Swagelok, Inc., SupplementalFigure S16) attached to a cylinder of compressed nitrogen 22. The teefilter is connected on the other end to the eSTAT nozzle 14, a ½″×⅜″Swagelok reducing union fitted to a modified ⅜″ Swagelok bulkhead union(Swagelok, Inc., Supplemental Figure S17) via ½″ (outer diameter)polypropylene tubing 16. Balloon(s) 4 are mounted in place under thebell jar 2. In this example, twelve 3.0 mm width balloons at a time arecoated with the positively charged milled sirolimus 6. The balloons 4may be of various lengths, such as lengths ranging from 17 mm to 23 mm,however, in other embodiments, other sizes may be used. In someembodiments, fewer or more balloons may be coated at a time. Theballoons 4 used during the coating process are typically mounted oncatheters having wires 10 disposed therein 8 which are coupled to a highvoltage power supply 12 (such as a Spellman SL30 high voltage powersupply), which may be set at −15 kV, for example.

In some embodiments, the lengths of the balloons may be any length from5 mm to 35 mm, or any of the following lengths, for example: about 5 mm,about 7 mm, about 8 mm, about 10 mm, about 12 mm, about 13 mm, about 15mm, about 18 mm, about 20 mm, about 21 mm, about 23 mm, about 25 mm,about 28 mm, about 30 mm, about 32 mm, about 33 mm, and about 35 mm. Theterm “about” when used in the context of balloon length, can meanvariations of for example, 10%, 25%, 50%, 0.1 mm, 0.25 mm, 0.5 mm, 1 mm,2 mm, and 5 mm, depending on the embodiment.

In some embodiments, the diameters (ie. widths) of the balloons may beany diameter from 1.5 mm to 6.0 mm, or any of the following diameters,for example: about 1.5 mm, about 1.8 mm, about 2.0 mm, about 2.25 mm,about 2.5 mm, about 2.75 mm, about 3.0 mm, about 3.25 mm, about 3.5 mm,about 3.75 mm, about 4.0 mm, about 4.25 mm, about 4.5 mm, about 4.75 mm,about 5.0 mm, about 5.25 mm, and about 5.5 mm. The term “about” whenused in the context of balloon diameter (or width), can mean variationsof for example, 10%, 25%, 50%, 0.1 mm, 0.25 mm, 0.3 mm, 0.4 mm, 0.5 mm,0.75 mm, 1 mm, and 2 mm, depending on the embodiment.

In some embodiments a minimum of one balloon is coated at a time. Insome embodiments, at least one of: at least 3 balloons, at least 5balloons, at least 6 balloons, at least 8 balloons, at least 10balloons, at least 12 balloons, at least 15 balloons, at least 16balloons, at least 20 balloons, at least 24 balloons, and at least 30balloons are coated at a time.

These balloons may or may not be pre-coated with a polymer, such asPLGA. Coating of the balloons may be achieved by various means, such asdip coating, spray coating, or coating using an RESS method. Forexample, a polymer (e.g. PLGA) is applied to the balloons via rapidexpansion of supercritical solutions (RESS), where the solute (e.g.PLGA) is dissolved in a supercritical fluid then rapidly expanded withsudden decompression by passing through a short nozzle into an area oflow temperature and pressure. These conditions cause the dissolved PLGAto rapidly precipitate as a fine powder with a narrow distribution ofparticle size resulting in a uniform coating on the angioplastyballoons.

FIG. 3 depicts an example RESS process for coating balloons 4 with PLGA.The PLGA is loaded into a vessel 24 in which it is dissolved in HFC236eafrom a HFC236ea cylinder 26 which is sent to the vessel 24 through asyringe pump 28 (for example, an Isco 260D syringe pump). The PLGA thusforms a supercritical solution with the HFC236 ea, which is stirred at ahigh pressure (5500 psi) in mixing view cells (50 cc). The PLGA solutionis sent through a syringe pump 30 (for example, an Isco 260D syringepump) which sends the solution through a heater block 32 (withtemperature control feedback) and then through a timed pneumatic valve34 which is heated at 137 C. The PLGA solution is then sent through acapillary tube 36 (e.g. PEEKsil capillary tube 1/16″ outer diameter by100 micron inner diameter by 10 cm long) which is surrounded by astainless steel sheath (e.g. ¼ inches thick stainless steel sheath). ThePLGA is then ejected through a nozzle 40 which is electrically grounded(for example, via a stainless steel sheath). When the PLGA solutionexits the nozzle 40, the PLGA is ejected as dry PLGA particles 42, asthe solution comprising PLGA and HFC236ea rapidly expands. The balloons4 used during the coating process are typically mounted on cathetershaving wires 10 disposed therein 8 which are electrically grounded 44.The wires 10 may be coupled to a high voltage power supply 12 (such as aSpellman SL30 high voltage power supply), in order to facilitate theeSTAT coating of the balloons with the active agent, however, during theRESS process described in this embodiment, the balloons are electricallygrounded and no current flows from the power supply 12.

When viewed in combination, FIGS. 2 and 3 indicate a single apparatusthat can both coat according to an RESS process and an eSTAT process.Elements called out and depicted in FIG. 2 may similarly be called outin FIG. 3, and vice versa. Alternatively, separate coating apparatusesmay be used to separately coat according to an RESS process and an eSTATprocess.

“Solution Enhanced Dispersion of Supercritical Solutions” or “SEDS” asused herein involves a spray process for the generation of polymerparticles, which are formed when a compressed fluid (e.g. supercriticalfluid, preferably supercritical CO₂) is used as a diluent to a vehiclein which a polymer is dissolved (one that can dissolve both the polymerand the compressed fluid). The mixing of the compressed fluid diluentwith the polymer-containing solution may be achieved by encounter of afirst stream containing the polymer solution and a second streamcontaining the diluent compressed fluid, for example, within one spraynozzle or by the use of multiple spray nozzles. The solvent in thepolymer solution may be one compound or a mixture of two or moreingredients and may be or comprise an alcohol (including diols, triols,etc.), ether, amine, ketone, carbonate, or alkanes, or hydrocarbon(aliphatic or aromatic) or may be a mixture of compounds, such asmixtures of alkanes, or mixtures of one or more alkanes in combinationwith additional compounds such as one or more alcohols, (e.g., from 0 or0.1 to 5% of a Ci to Ci₅ alcohol, including diols, triols, etc.). Seefor example U.S. Pat. No. 6,669,785, incorporated herein by reference inits entirety. The solvent may optionally contain a surfactant, as alsodescribed in, e.g., U.S. Pat. No. 6,669,785.

In one embodiment of the SEDS process, a first stream of fluidcomprising a polymer dissolved in a common solvent is co-sprayed with asecond stream of compressed fluid. Polymer particles are produced as thesecond stream acts as a diluent that weakens the solvent in the polymersolution of the first stream. The now combined streams of fluid, alongwith the polymer particles, flow out of the nozzle assembly into acollection vessel. Control of particle size, particle size distribution,and morphology is achieved by tailoring the following process variables:temperature, pressure, solvent composition of the first stream,flow-rate of the first stream, flow-rate of the second stream,composition of the second stream (where soluble additives may be addedto the compressed gas), and conditions of the capture vessel. Typicallythe capture vessel contains a fluid phase that is at least five to tentimes (5-10×) atmospheric pressure.

“Electrostatic Dry Powder Coating” or “e-DPC” or “eDPC” as used hereinrefers to Electrostatic Capture as described herein combined with DryPowder Coating. e-DPC deposits material (including, for example, polymeror impermeable dispersed solid) on the device or other substrate as drypowder, using electrostatic capture to attract the powder particles tothe substrate. Dry powder spraying (“Dry Powder Coating” or “DPC”) iswell known in the art, and dry powder spraying coupled withelectrostatic capture has been described, for example in U.S. Pat. Nos.5,470,603, 6,319,541, and 6,372,246, all incorporated herein byreference in their entirety. Methods for depositing coatings aredescribed, e.g., in WO 2008/148013, “Polymer Films for Medical DeviceCoating,” incorporated herein by reference in its entirety.

“Dipping Process” and “Spraying Process” as used herein refer to methodsof coating substrates that have been described at length in the art.These processes can be used for coating medical devices withpharmaceutical agents. Spray coating, described in, e.g., U.S. Pat. No.7,419,696, “Medical devices for delivering a therapeutic agent andmethod of preparation” and elsewhere herein, can involve spraying orairbrushing a thin layer of solubilized coating or dry powder coatingonto a substrate. Dip coating involves, e.g., dipping a substrate in aliquid, and then removing and drying it. Dip coating is described in,e.g., U.S. Pat. No. 5,837,313 “Drug release stent coating process,”incorporated herein by reference in its entirety.

“Bulk properties” properties of a coating including a pharmaceutical ora biological agent that can be enhanced through the methods of theinvention include for example: adhesion, smoothness, conformality,thickness, and compositional mixing.

“Electrostatically charged” or “electrical potential” or “electrostaticcapture” as used herein refers to the collection of the spray-producedparticles upon a substrate that has a different electrostatic potentialthan the sprayed particles. Thus, the substrate is at an attractiveelectronic potential with respect to the particles exiting, whichresults in the capture of the particles upon the substrate. i.e. thesubstrate and particles are oppositely charged, and the particlestransport through the gaseous medium of the capture vessel onto thesurface of the substrate is enhanced via electrostatic attraction. Thismay be achieved by charging the particles and grounding the substrate orconversely charging the substrate and grounding the particles, bycharging the particles at one potential (e.g. negative charge) andcharging the substrate at an opposite potential (e.g. positive charge),or by some other process, which would be easily envisaged by one ofskill in the art of electrostatic capture.

“Depositing the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess without electrically charging the substrate” as used hereinrefers to any of these processes as performed without intentionallyelectrically charging the substrate. It is understood that the substratemight become electrically charged unintentionally during any of theseprocesses.

“Depositing the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess without creating an electrical potential between the substrateand a coating apparatus” as used herein refers to any of these processesas performed without intentionally generating an electrical potentialbetween the substrate and the coating apparatus. It is understood thatelectrical potential between the substrate and the coating apparatusmight be generated unintentionally during any of these processes.

“Intimate mixture” as used herein, refers to two or more materials,compounds, or substances that are uniformly distributed or dispersedtogether.

“Layer” as used herein refers to a material covering a surface orforming an overlying part or segment. Two different layers may haveoverlapping portions whereby material from one layer may be in contactwith material from another layer. Contact between materials of differentlayers can be measured by determining a distance between the materials.For example, Raman spectroscopy may be employed in identifying materialsfrom two layers present in close proximity to each other.

While layers defined by uniform thickness and/or regular shape arecontemplated herein, several embodiments described herein relate tolayers having varying thickness and/or irregular shape. Material of onelayer may extend into the space largely occupied by material of anotherlayer. For example, in a coating having three layers formed in sequenceas a first polymer layer, a pharmaceutical agent layer and a secondpolymer layer, material from the second polymer layer which is depositedlast in this sequence may extend into the space largely occupied bymaterial of the pharmaceutical agent layer whereby material from thesecond polymer layer may have contact with material from thepharmaceutical layer. It is also contemplated that material from thesecond polymer layer may extend through the entire layer largelyoccupied by pharmaceutical agent and contact material from the firstpolymer layer.

It should be noted however that contact between material from the secondpolymer layer (or the first polymer layer) and material from thepharmaceutical agent layer (e.g.; a pharmaceutical agent crystalparticle or a portion thereof) does not necessarily imply formation of amixture between the material from the first or second polymer layers andmaterial from the pharmaceutical agent layer. In some embodiments, alayer may be defined by the physical three-dimensional space occupied bycrystalline particles of a pharmaceutical agent (and/or biologicalagent). It is contemplated that such layer may or may not be continuousas physical space occupied by the crystal particles of pharmaceuticalagents may be interrupted, for example, by polymer material from anadjacent polymer layer. An adjacent polymer layer may be a layer that isin physical proximity to be pharmaceutical agent particles in thepharmaceutical agent layer. Similarly, an adjacent layer may be thelayer formed in a process step right before or right after the processstep in which pharmaceutical agent particles are deposited to form thepharmaceutical agent layer.

As described herein, material deposition and layer formation providedherein are advantageous in that the pharmaceutical agent remains largelyin crystalline form during the entire process. While the polymerparticles and the pharmaceutical agent particles may be in contact, thelayer formation process is controlled to avoid formation of a mixturebetween the pharmaceutical agent particles the polymer particles duringformation of a coated device.

In some embodiments, the coating comprises a plurality of layersdeposited on the substrate, wherein at least one of the layers comprisesthe active agent. In some embodiments, at least one of the layerscomprises a polymer. In some embodiments, the polymer is bioabsorbable.In some embodiments, the active agent and the polymer are in the samelayer, in separate layers, or form overlapping layers. In someembodiments, the plurality of layers comprise five layers deposited asfollows: a first polymer layer, a first active agent layer, a secondpolymer layer, a second active agent layer and a third polymer layer.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a plurality of layers deposited on the substrate,wherein at least one of the layers comprises the active agent. In someembodiments, at least one of the layers comprises a polymer. In someembodiments, the polymer is bioabsorbable. In some embodiments, theactive agent and the polymer are in the same layer, in separate layers,or form overlapping layers. In some embodiments, the coating comprises aplurality of layers deposited on the substrate, wherein at least one ofthe layers comprises the pharmaceutical agent. In some embodiments, thepharmaceutical agent and the polymer are in the same layer, in separatelayers, or form overlapping layers. In some embodiments, the pluralityof layers comprise five layers deposited as follows: a first polymerlayer, a first active agent layer, a second polymer layer, a secondactive agent layer and a third polymer layer. In some embodiments, theplurality of layers comprise five layers deposited as follows: a firstpolymer layer, a first pharmaceutical agent layer, a second polymerlayer, a second pharmaceutical agent layer and a third polymer layer. Insome embodiments, the plurality of layers comprise five layers depositedas follows: a first polymer layer, a first active biological agentlayer, a second polymer layer, a second active biological agent layerand a third polymer layer.

In some embodiments, the device provides the coating to the interventionsite over an area of delivery greater than the outer surface contactarea of the substrate. In some embodiments, the area of delivery is atleast 110% greater than the outer surface contact area of the substrate.In some embodiments, the area of delivery is at least 110% to 200%greater than the outer surface contact area of the substrate. In someembodiments, the area of delivery is at least 200% greater than theouter surface contact area of the substrate.

“Laminate coating” as used herein refers to a coating made up of two ormore layers of material. Means for creating a laminate coating asdescribed herein (e.g.; a laminate coating comprising bioabsorbablepolymer(s) and pharmaceutical agent) may include coating the stent withdrug and polymer as described herein (e-RESS, e-DPC, compressed-gassintering). The process comprises performing multiple and sequentialcoating steps (with sintering steps for polymer materials) whereindifferent materials may be deposited in each step, thus creating alaminated structure with a multitude of layers (at least 2 layers)including polymer layers and pharmaceutical agent layers to build thefinal device (e.g.; laminate coated stent).

“Portion of the coating” and “portion of the active agent” as usedherein refer to an amount or percentage of the coating or active agentthat is freed, dissociated, and/or transferred from the substrate to theintervention site, either at a designated point in delivery, during acertain period of delivery, or in total throughout the entire deliveryprocess. In embodiments, the device and methods of the invention areadapted to free, dissociate, and/or transfer a certain amount of thecoating and/or active agent.

For example, in embodiments, at least about 10%, at least about 20%, atleast about 30%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating is adapted to be freed, dissociated, and/or to betransferred from the substrate to the intervention site. In embodiments,at least about 10%, at least about 20%, at least about 30%, at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%, and/or at least about 99% of the active agent isadapted to be freed, dissociated, and/or to be transferred from thesubstrate to the intervention site.

The portion of the coating and/or that is freed, dissociated, ortransferred from the device substrate is influenced by any or acombination of, e.g., the size, shape, and flexibility of the devicesubstrate, the size, shape, surface qualities of and conditions (e.g.,blood or lymph circulation, temperature, etc.) at the intervention site,the composition of the coating, including the particular active agent(s)and specific polymer component(s) used in the coating, the relativeproportions of these components, the use of any release agent(s), andsubstrate characteristics. Any one or more of these and other aspects ofthe device and methods of the invention can be adapted to influence theportion of the coating and/or active agent freed, dissociated, and/ortransferred, as desired to produce the desired clinical outcome.

“Substantially all of the coating” as used herein refers to at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%, at least about 97%, and/or at least about 99%percent of the coating that was present on the device prior to use.

“At least a portion of the substrate” as used herein refers to an amountand/or percentage of the substrate. In embodiments of the device andmethods of the invention wherein a coating is on “at least a portion ofthe substrate,” at least about 10%, at least about 20%, at least about30%, at least about 50%, at least about 75%, at least about 85%, atleast about 90%, at least about 95%, and/or at least about 99% of thesubstrate is coated. In embodiments wherein “at least a portion of thesubstrate” is bioabsorbable, at least about 10%, at least about 20%, atleast about 30%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the substrate is bioabsorbable.

“Transferring at least a portion” as used herein in the context oftransferring a coating or active agent from the substrate to anintervention site refers to an amount and/or percentage of the coatingor active agent that is transferred from the substrate to anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating or active agent istransferred from the substrate to an intervention site, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating or active agent istransferred from the substrate to the intervention site. In someembodiments, at least about 10%, at least about 20%, at least about 30%,at least about 50%, at least about 75%, at least about 85%, at leastabout 90%, at least about 95%, and/or at least about 99% of the coatingis adapted to transfer from the substrate to the intervention site. Insome embodiments, at least about 10% of the coating is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 20% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 30% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 50% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 75% of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 85% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 90% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 95% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 99% of the coating is adaptedto transfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating transferred, or as a variation of thepercentage of the coating transferred).

In some embodiments, the coating portion that is adapted to transferupon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, device is adapted to transferless than about 1%, less than about 5%, less than about 10%. less thanabout 15%, less than about 25%, less than about 50%, less than about70%, less than about 80%, and/or less than about 90% of the coatingabsent stimulation of the coating.

In some embodiments, at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of theactive agent is adapted to transfer from the substrate to theintervention site. In some embodiments, at least about 10% of the activeagent is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 20% of the active agent isadapted to transfer from the substrate to the intervention site. In someembodiments, at least about 30% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 50% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 75% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 85% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 90% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 95% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 99% of the active agent is adapted totransfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the active agent canmean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as apercent of the percentage of the active agent transferred, or as avariation of the percentage of the active agent transferred).

In some embodiments, the active agent portion that is adapted totransfer upon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, the device is adapted totransfer less than about 1%, less than about 5%, less than about 10%.less than about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, and/or less than about 90% of the activeagent absent stimulation of the coating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 10% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 20% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 30% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 50% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 75% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 85% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 90% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 95% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 99% of the coating from the substrate to theintervention site. As used herein, “about” when used in reference to apercentage of the coating can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of thecoating transferred, or as a variation of the percentage of the coatingtransferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 10% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 20% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 30% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 50% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 75% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 85% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 90% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 95% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 99% of the active agent from the substrate tothe intervention site. As used herein, “about” when used in reference toa percentage of the active agent can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of the activeagent transferred, or as a variation of the percentage of the activeagent transferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, the stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%, lessthan about 90% of the active agent absent stimulation of the coating.

“Freeing at least a portion” as used herein in the context of freeing acoating and/or active agent from the substrate at an intervention siterefers to an amount and/or percentage of a coating or active agent thatis freed from the substrate at an intervention site. In embodiments ofthe device and methods of the invention wherein at least a portion of acoating or active agent is freed from the substrate at an interventionsite, at least about 10%, at least about 20%, at least about 30%, atleast about 50%, at least about 75%, at least about 85%, at least about90%, at least about 95%, and/or at least about 99% of the coating oractive agent is freed from the substrate at the intervention site. Insome embodiments, the device is adapted to free at least about 10%, atleast about 20%, at least about 30%, at least about 50%, at least about75%, at least about 85%, at least about 90%, at least about 95%, and/orat least about 99% of the coating from the substrate. In someembodiments, the device is adapted to free at least about 10% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 20% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 30% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 50% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 75% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 85% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 90% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 95% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 99% of thecoating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating freed, or as a variation of thepercentage of the coating freed).

In some embodiments, the coating portion that frees upon stimulation ison at least one of a distal surface of the substrate, a middle surfaceof the substrate, a proximal surface of the substrate, and an abluminalsurface of the substrate.

In some embodiments, the stimulation decreases the contact between thecoating and the substrate. In some embodiments, the device is adapted tofree less than about 1%, less than about 5%, less than about 10%. lessthan about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, less than about 90% of the coatingabsent stimulation of the coating.

“Dissociating at least a portion” as used herein in the context ofdissociating a coating and/or active agent from the substrate at anintervention site refers to an amount and/or percentage of a coatingand/or active agent that is dissociated from the substrate at anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdissociated from the substrate at an intervention site, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating and/or active agent isdissociated from the substrate at the intervention site.

In some embodiments, the device is adapted to dissociate at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate. Insome embodiments, the device is adapted to dissociate at least about 10%of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 20% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 30% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 50% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 75% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 85% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 90% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 95% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 99% ofthe coating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating dissociated, or as a variation of thepercentage of the coating dissociated).

In some embodiments, the coating portion that dissociates uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments,stimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to dissociate less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

“Depositing at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is deposited atan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdeposited at an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is deposited at theintervention site. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,depositing deposits less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, less than about50%, less than about 70%, less than about 80%, and/or less than about90% of the coating absent stimulating at least one of the coating andthe substrate.

“Delivering at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is delivered toan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdelivered to an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is delivered to theintervention site.

In some embodiments, the device is adapted to deliver at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating to the intervention site.In some embodiments, the device is adapted to deliver at least about 10%of the coating to the intervention site. In some embodiments, the deviceis adapted to deliver at least about 20% of the coating to theintervention site. In some embodiments, the device is adapted to deliverat least about 30% of the coating to the intervention site. In someembodiments, the device is adapted to deliver at least about 50% of thecoating to the intervention site. In some embodiments, the device isadapted to deliver at least about 75% of the coating to the interventionsite. In some embodiments, the device is adapted to deliver at leastabout 85% of the coating to the intervention site. In some embodiments,the device is adapted to deliver at least about 90% of the coating tothe intervention site. In some embodiments, the device is adapted todeliver at least about 95% of the coating to the intervention site. Insome embodiments, the device is adapted to deliver at least about 99% ofthe coating to the intervention site. As used herein, “about” when usedin reference to a percentage of the coating can mean ranges of 1%-5%, of5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of the percentage ofthe coating delivered, or as a variation of the percentage of thecoating delivered).

In some embodiments, the coating portion that is delivered uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments, thestimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to deliver less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, depositing at least a portion of the coatingcomprises depositing at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of thecoating at the intervention site. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, depositing deposits less than about 1%, less than about 5%,less than about 10%. less than about 15%, less than about 25%, less thanabout 50%, less than about 70%, less than about 80%, and/or less thanabout 90% of the coating absent stimulating at least one of the coatingand the substrate.

“Tacking at least a portion” as used herein in the context of tacking atleast a portion of the coating to an intervention site refers to anamount and/or percentage of a coating and/or active agent that is tackedat an intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent istacked at an intervention site, at least about 10%, at least about 20%,at least about 30%, at least about 50%, at least about 75%, at leastabout 85%, at least about 90%, at least about 95%, and/or at least about99% of the coating and/or active agent is tacked at the interventionsite. In some embodiments, stimulating decreases the contact between thecoating and the substrate. In some embodiments, tacking tacks less thanabout 1%, less than about 5%, less than about 10%. less than about 15%,less than about 25%, less than about 50%, less than about 70%, less thanabout 80%, and/or less than about 90% of the coating absent stimulatingat least one of the coating and the substrate. In some embodiments, thedevice comprises a tacking element that cooperates with the stimulationto tack the coating to the intervention site. In some embodiments, thedevice comprises a tacking element that tacks the coating to thesubstrate until stimulating with a stimulation.

“Adhere,” “adherence,” “adhered,” “cohere,” “coherence,” “cohered,” andrelated terms, as used herein in the context of adherence or coherenceof the substrate to the coating refer to an interaction between thesubstrate and the coating that is sufficiently strong to maintain theassociation of the coating with the substrate for an amount of timeprior to the stimulation, e.g., mechanical, chemical, thermal,electromagnetic, or sonic stimulation, that is intended to cause thecoating to be freed, dissociated, and/or transferred. These same terms,as used in the context of an interaction between the coating and thetarget tissue area and/or intervention site refer to an interactionbetween the coating and the target tissue area and/or intervention sitethat is sufficient to keep the coating associated with the target tissuearea and/or intervention site for an amount of time as desired fortreatment, e.g., at least about 12 hours, about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

“Balloon” as used herein refers to a flexible sac that can be inflatedwithin a natural or non-natural body lumen or cavity, or used to createa cavity, or used to enlarge an existing cavity. The balloon can be usedtransiently to dilate a lumen or cavity and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In embodiments, the balloon can be expanded within the bodyand has a coating thereon that is freed (at least in part) from theballoon and left behind in the lumen or cavity when the balloon isremoved. A coating can be applied to a balloon either after the balloonhas been compacted for insertion, resulting in a coating that partiallycovers the surface of the balloon, or it can be applied prior to orduring compaction. In embodiments, a coating is applied to the balloonboth prior to and after compaction of the balloon. In embodiments, theballoon is compacted by, e.g., crimping or folding. Methods ofcompacting balloons have been described, e.g., in U.S. Pat. No.7,308,748, “Method for compressing an intraluminal device,” and U.S.Pat. No. 7,152,452, “Assembly for crimping an intraluminal device andmethod of use,” relating to uniformly crimping a balloon onto a catheteror other intraluminal device, and U.S. Pat. No. 5,350,361 “Tri-foldballoon for dilatation catheter and related method,” relating to balloonfolding methods and devices, all incorporated herein by reference intheir entirety. In some embodiments the balloon is delivered to theintervention site by a delivery device. In some embodiments, thedelivery device comprises catheter. In some embodiments, the balloon isan angioplasty balloon. Balloons can be delivered, removed, andvisualized during delivery and removal by methods known in the art,e.g., for inserting angioplasty balloons, stents, and other medicaldevices. Methods for visualizing a treatment area and planninginstrument insertion are described, e.g., in U.S. Pat. No. 7,171,255,“Virtual reality 3D visualization for surgical procedures” and U.S. Pat.No. 6,610,013, “3D ultrasound-guided intraoperative prostatebrachytherapy,” incorporated herein by reference in their entirety.

“Compliant balloon” as used herein refers to a balloon which conforms tothe intervention site relatively more than a semi-compliant balloon andstill more so than a non-compliant balloon. Compliant balloons expandand stretch with increasing pressure within the balloon, and are madefrom such materials as polyethylene or polyolefin copolymers. There isin the art a general classification of balloons based on theirexpandability or “compliance” relative to each other, as described e.g.,in U.S. Pat. No. 5,556,383, “Block copolymer elastomer catheterballoons.” Generally, “non-compliant” balloons are the least elastic,increasing in diameter about 2-7%, typically about 5%, as the balloon ispressurized from an inflation pressure of about 6 atm to a pressure ofabout 12 atm, that is, they have a “distension” over that pressure rangeof about 5%. “Semi-compliant” balloons have somewhat greaterdistensions, generally 7-16% and typically 10-12% over the samepressurization range. “Compliant” balloons are still more distensible,having distensions generally in the range of 16-40% and typically about21% over the same pressure range. Maximum distensions, i.e. distensionfrom nominal diameter to burst, of various balloon materials may besignificantly higher than the distension percentages discussed abovebecause wall strengths, and thus burst pressures, vary widely betweenballoon materials. These distension ranges are intended to providegeneral guidance, as one of skill in the art will be aware that thecompliance of a balloon is dependent on the dimensions and/orcharacteristics of the cavity and/or lumen walls, not only theexpandability of the balloon.

A compliant balloon may be used in the vasculature of a subject. Acompliant balloon might also be used in any tube or hole outside thevasculature (whether naturally occurring or man-made, or created duringan injury). For a non-limiting example, a compliant balloon might beused in a lumpectomy to put a coating at the site where a tumor wasremoved, to: treat an abscess, treat an infection, prevent an infection,aid healing, promote healing, or for a combination of any of thesepurposes. The coating in this embodiment may comprise a growth factor.

“Non-Compliant balloon” as used herein refers to a balloon that does notconform to the intervention site, but rather, tends to cause theintervention site to conform to the balloon shape. Non-compliantballoons, commonly made from such materials as polyethyleneterephthalate (PET) or polyamides, remain at a preselected diameter asthe internal balloon pressure increases beyond that required to fullyinflate the balloon. Non-compliant balloons are often used to dilatespaces, e.g., vascular lumens. As noted with respect to a compliantballoon, one of skill in the art will be aware that the compliance of aballoon is dependent on the dimensions and/or characteristics of thecavity and/or lumen walls, not only the expandability of the balloon.

“Cutting balloon” as used herein refers to a balloon commonly used inangioplasty having a special balloon tip with cutting elements, e.g.,small blades, wires, etc. The cutting elements can be activated when theballoon is inflated. In angioplasty procedures, small blades can be usedscore the plaque and the balloon used to compress the fatty matteragainst the vessel wall. A cutting balloon might have tacks or otherwire elements which in some embodiments aid in freeing the coating fromthe balloon, and in some embodiments, may promote adherence or partialadherence of the coating to the target tissue area, or some combinationthereof. In some embodiments, the cutting balloon cutting elements alsoscore the target tissue to promote the coating's introduction into thetarget tissue. In some embodiments, the cutting elements do not cuttissue at the intervention site. In some embodiments, the cuttingballoon comprises tacking elements as the cutting elements.

“Inflation pressure” as used herein refers to the pressure at which aballoon is inflated. As used herein the nominal inflation pressurerefers to the pressure at which a balloon is inflated in order toachieve a particular balloon dimension, usually a diameter of theballoon as designed. The “rated burst pressure” or “RBP” as used hereinrefers to the maximum statistically guaranteed pressure to which aballoon can be inflated without failing. For PTCA and PTA catheters, therated burst pressure is based on the results of in vitro testing to thePTCA and/or PTA catheters, and normally means that at least 99.9% of theballoons tested (with 95% confidence) will not burst at or below thispressure.

“Tacking element” as used herein refers to an element on the substratesurface that is used to influence transfer of the coating to theintervention site. For example, the tacking element can comprise aprojection, e.g., a bump or a spike, on the surface of the substrate. Inembodiments, the tacking element is adapted to secure the coating to thecutting balloon until inflation of the cutting balloon. In someembodiments, tacking element can comprise a wire, and the wire can beshaped in the form of an outward pointing wedge. In certain embodiments,the tacking element does not cut tissue at the intervention site.

As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to:As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to: aknife, a scalpel, a guidewire, a guiding catheter, a introductioncatheter, a distracter, a needle, a syringe, a biopsy device, anarticulator, a Galotti articulator, a bone chisel, a bone crusher, acottle cartilage crusher, a bone cutter, a bone distractor, an Ilizarovapparatus, an intramedullary kinetic bone distractor, a bone drill, abone extender, a bone file, a bone lever, a bone mallet, a bone rasp, abone saw, a bone skid, a bone splint, a bone button, a caliper, acannula, a catheter, a cautery, a clamp, a coagulator, a curette, adepressor, a dilator, a dissecting knife, a distractor, a dermatome,forceps, dissecting forceps, tissue forceps, sponge forceps, boneforceps, Carmalt forceps, Cushing forceps, Dandy forceps, DeBakeyforceps, Doyen intestinal forceps, epilation forceps, Halstead forceps,Kelly forceps, Kocher forceps, mosquito forceps, a hemostat, a hook, anerve hook, an obstetrical hook, a skin hook, a hypodermic needle, alancet, a luxator, a lythotome, a lythotript, a mallet, a partschmallet, a mouth prop, a mouth gag, a mammotome, a needle holder, anoccluder, an osteotome, an Epker osteotome, a periosteal elevator, aJoseph elevator, a Molt periosteal elevator, an Obweg periostealelevator, a septum elevator, a Tessier periosteal elevator, a probe, aretractor, a Senn retractor, a Gelpi retractor, a Weitlaner retractor, aUSA-Army/Navy retractor, an O'Connor-O'Sullivan retractor, a Deaverretractor, a Bookwalter retractor, a Sweetheart retractor, a Joseph skinhook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rakeretractor, a flexible rake retractor, a Ragnell retractor, aLinde-Ragnell retractor, a Davis retractor, a Volkman retractor, aMathieu retractor, a Jackson tracheal hook, a Crile retractor, aMeyerding finger retractor, a Little retractor, a Love Nerve retractor,a Green retractor, a Goelet retractor, a Cushing vein retractor, aLangenbeck retractor, a Richardson retractor, a Richardson-Eastmannretractor, a Kelly retractor, a Parker retractor, a Parker-Mottretractor, a Roux retractor, a Mayo-Collins retractor, a Ribbonretractor, an Alm retractor, a self retaining retractor, a Weitlanerretractor, a Beckman-Weitlaner retractor, a Beckman-Eaton retractor, aBeckman retractor, an Adson retractor, a rib spreader, a rongeur, ascalpel, an ultrasonic scalpel, a laser scalpel, scissors, irisscissors, Kiene scissors, Metzenbaum scissors, Mayo scissors, Tenotomyscissors, a spatula, a speculum, a mouth speculum, a rectal speculum,Sim's vaginal speculum, Cusco's vaginal speculum, a sternal saw, asuction tube, a surgical elevator, a surgical hook, a surgical knife,surgical mesh, a surgical needle, a surgical snare, a surgical sponge, asurgical spoon, a surgical stapler, a suture, a syringe, a tonguedepressor, a tonsillotome, a tooth extractor, a towel clamp, towelforceps, Backhaus towel forceps, Lorna towel forceps, a tracheotome, atissue expander, a subcutaneous inflatable balloon expander, a trephine,a trocar, tweezers, and a venous clipping. In some embodiments, asurgical tool may also and/or alternatively be referred to as a tool forperforming a medical procedure. In some embodiments, a surgical tool mayalso and/or alternatively be a tool for delivering to the interventionsite a biomedical implant.

“Stimulation” as used herein refers to any mechanical stimulation,chemical stimulation, thermal stimulation, electromagnetic stimulation,and/or sonic stimulation that influences, causes, initiates, and/orresults in the freeing, dissociation, and/or the transfer of the coatingand/or active agent from the substrate.

“Mechanical Stimulation” as used herein refers to use of a mechanicalforce that influences the freeing, dissociation, and/or transfer of thecoating and/or the active agent from the substrate. For example,mechanical stimulation can comprise a shearing force, a compressiveforce, a force exerted on the coating from a substrate side of thecoating, a force exerted on the coating by the substrate, a forceexerted on the coating by an external element, a translation, arotation, a vibration, or a combination thereof. In embodiments, themechanical stimulation comprises balloon expansion, stent expansion,etc. In embodiments, the mechanical stimulation is adapted to augmentthe freeing, dissociation and/or transfer of the coating from thesubstrate. In embodiments, the mechanical stimulation is adapted toinitiate the freeing, dissociation and/or transfer of the coating fromthe substrate. In embodiments, the mechanical stimulation can be adaptedto cause the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, an external element is a part of thesubject. In embodiments, the external element is not part of the device.In embodiments the external element comprises a liquid, e.g., saline orwater. In certain embodiments the liquid is forced between the coatingand the substrate. In embodiments, the mechanical stimulation comprisesa geometric configuration of the substrate that maximizes a shear forceon the coating.

“Chemical Stimulation” as used herein refers to use of a chemical forceto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, chemical stimulation can comprise bulkdegradation, interaction with a bodily fluid, interaction with a bodilytissue, a chemical interaction with a non-bodily fluid, a chemicalinteraction with a chemical, an acid-base reaction, an enzymaticreaction, hydrolysis, or a combination thereof. In embodiments, thechemical stimulation is adapted to augment the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to initiate the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to cause the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is achieved through the use of a coating thatcomprises a material that is adapted to transfer, free, and/ordissociate from the substrate when at the intervention site in responseto an in-situ enzymatic reaction resulting in a weak bond between thecoating and the substrate.

“Thermal Stimulation” as used herein refers to use of a thermal stimulusto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, thermal stimulation can comprise atleast one of a hot stimulus and a cold stimulus. In embodiments, thermalstimulation comprises at least one of a hot stimulus and a cold stimulusadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, thermal stimulationcomprises at least one of a hot stimulus and a cold stimulus adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, thermal stimulation comprises atleast one of a hot stimulus and a cold stimulus adapted to cause thefreeing, dissociation and/or transference of the coating from thesubstrate.

“Electromagnetic Stimulation” as used herein refers to use of anelectromagnetic stimulus to influence the freeing, dissociation, and/ortransfer of the coating from the substrate. For example, theelectromagnetic stimulation is an electromagnetic wave comprising atleast one of, e.g., a radio wave, a micro wave, a infrared wave, nearinfrared wave, a visible light wave, an ultraviolet wave, a X-ray wave,and a gamma wave. In embodiments, the electromagnetic stimulation isadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, the electromagneticstimulation is adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In embodiments, theelectromagnetic stimulation is adapted to cause the freeing,dissociation and/or transference of the coating from the substrate.

“Sonic Stimulation” as used herein refers to use of a sonic stimulus toinfluence the freeing, dissociation, and/or transfer of the coating fromthe substrate. For example, sonic stimulation can comprise a sound wave,wherein the sound wave is at least one of an ultrasound wave, anacoustic sound wave, and an infrasound wave. In embodiments, the sonicstimulation is adapted to augment the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the sonicstimulation is adapted to initiate the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the sonicstimulation is adapted to cause the freeing, dissociation and/ortransfer of the coating from the substrate.

“Release Agent” as used herein refers to a substance or substratestructure that influences the ease, rate, or extent, of release of thecoating from the substrate. In certain embodiments wherein the device isadapted to transfer a portion of the coating and/or active agent fromthe substrate to the intervention site, the device can be so adapted by,e.g., substrate attributes and/or surface modification of the substrate(for non-limiting example: substrate composition, substrate materials,substrate shape, substrate deployment attributes, substrate deliveryattributes, substrate pattern, and/or substrate texture), the deliverysystem of the substrate and coating (for non-limiting example: controlover the substrate, control over the coating using the delivery system,the type of delivery system provided, the materials of the deliverysystem, and/or combinations thereof), coating attributes and/or physicalcharacteristics of the coating (for non-limiting example: selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute), release agent attributes (for non-limitingexample: through the selection a particular release agent and/or themanner in which the release agent is employed to transfer the coatingand/or the active agent, and/or the amount of the release agent used),and/or a combination thereof. Release agents may include biocompatiblerelease agents, non-biocompatible release agents to aggravate and/orotherwise induce a healing response or induce inflammation, powderrelease agents, lubricants (e.g. ePTFE, sugars, other known lubricants),micronized drugs as the release agent (to create a burst layer after thecoating is freed from the substrate, physical release agents (patterningof the substrate to free the coating, others), and/or agents that changeproperties upon insertion (e.g. gels, lipid films, vitamin E, oil,mucosal adhesives, adherent hydrogels, etc.). Methods of patterning asubstrate are described, e.g., in U.S. Pat. No. 7,537,610, “Method andsystem for creating a textured surface on an implantable medicaldevice.” In embodiments, more than one release agent is used, forexample, the substrate can be patterned and also lubricated. In someembodiments, the release agent comprises a viscous fluid.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid. In someembodiments, the viscous fluid is a fluid that is viscous relative tosaline. In some embodiments, the viscous fluid is a fluid that isviscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

“Extrusion” and/or “Extruded” and/or to “Extrude” as used herein refersto the movement of a substance away from another substance or object,especially upon stimulation, e.g., by a mechanical force. For example,in embodiments of the invention, the coating is extruded from thesubstrate.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to free from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to dissociate from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to transfer from the substrate to anintervention site upon stimulation of the coating.

In some embodiments, the patterned coating comprises at least twodifferent shapes.

“Patterned” as used herein in reference to the coating refers to acoating having at least two different shapes. The shapes can be formedby various methods, including for example, etching, masking,electrostatic capture, and/or by the coating methods described herein.For example the coating may have voids that are at least partiallythrough the thickness of the coating. In some embodiments, the voidsextend fully through the coating. The voids may be in a regularconfiguration, or irregular in shape. The voids may form a repeatingconfiguration to form the patterned coating. The voids may have beenremoved from a smooth or solid coating to form a patterned coating. Thecoating may in some embodiments be patterned by having a surface that isribbed, wavy or bumpy. The coating may in some embodiments be patternedby having been cut and/or etched from a coating sheath and/or sheet in aparticular design. The sheath and/or sheet in such embodiments may havebeen formed using the coating methods for manufacture as describedherein. The pattern design may be chosen to improve the freeing,transfer, and/or dissociation from the substrate. The pattern design maybe chosen to improve the transfer and/or delivery to the interventionsite.

Patterned coatings may be created using the methods and processesdescribed herein, for non-limiting example, by providing a substratehaving a patterned design thereon comprising, for example, a materialthat is chosen to selectively capture the coating particles (whetheractive agent, polymer, or other coating particles) to coat only adesired portion of the substrate. This portion that is coated may be thepatterned design of the substrate.

The term “image enhanced polymer” or “imaging agent” as used hereinrefer to an agent that can be used with the devices and methods of theinvention to view at least one component of the coating, either whilethe coating is on the substrate or after it is freed, dissociated and/ortransferred. In embodiments, an image enhanced polymer serves as atracer, allowing the movement or location of the coated device to beidentified, e.g., using an imaging system. In other embodiments, animage enhanced polymer allows the practitioner to monitor the deliveryand movement of a coating component. In embodiments, use of an imageenhanced polymer enables the practitioner to determine the dose of acomponent of the coating (e.g., the active agent) that is freed,dissociated and/or transferred. Information provided by the imageenhanced polymer or imaging agent about the amount of coatingtransferred to the intervention site can allow the practitioner todetermine the rate at which the coating will be released, therebyallowing prediction of dosing over time. Imaging agents may comprisebarium compounds such as, for non-limiting example, barium sulfate.Imaging agents may comprise iodine compounds. Imaging agents maycomprise any compound that improves radiopacity.

In embodiments, an image enhanced polymer is used with the device andmethods of the invention for a purpose including, but not limited to,one or more of the following: monitoring the location of the substrate,e.g., a balloon or other device; assessing physiological parameters,e.g., flow and perfusion; and targeting to a specific molecule. Inembodiments, “smart” agents that activate only in the presence of theirintended target are used with the device and methods of the invention.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and tacking at least a portion of the coating to anintervention site. In some embodiments, the tacking the coating portion(i.e. the portion of the coating) to the intervention site is uponstimulating the coating with a stimulation.

In some embodiments, the substrate comprises a balloon. In someembodiments, the portion of the balloon having coating thereon comprisesan outer surface of the balloon. In some embodiments, the outer surfaceis a surface of the balloon exposed to a coating prior to balloonfolding. In some embodiments, the outer surface is a surface of theballoon exposed to a coating following balloon folding. In someembodiments, the outer surface is a surface of the balloon exposed to acoating following balloon crimping. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at pressuresprovided by inflation of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at a pressurethat is less than the rated burst pressure of the balloon.

In some embodiments, the coating comprises a material that undergoesplastic deformation at a pressure that is less than the nominalinflation pressure of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation with at least 8ATM of pressure. In some embodiments, the coating comprises a materialthat undergoes plastic deformation with at least 6 ATM of pressure. Insome embodiments, the coating comprises a material that undergoesplastic deformation with at least 4 ATM of pressure. In someembodiments, the coating comprises a material that undergoes plasticdeformation with at least 2 ATM of pressure.

In some embodiments, the balloon is a compliant balloon. In someembodiments, the balloon is a semi-compliant balloon. In someembodiments, the balloon is a non-compliant balloon. In someembodiments, the balloon conforms to a shape of the intervention site.

In some embodiments, the balloon comprises a cylindrical portion. Insome embodiments, the balloon comprises a substantially sphericalportion. In some embodiments, the balloon comprises a complex shape. Insome embodiments, the complex shape comprises at least one of a doublenoded shape, a triple noded shape, a waisted shape, an hourglass shape,and a ribbed shape.

Some embodiments provide devices that can serve interventional purposesin addition to delivery of therapeutics, such as a cutting balloon. Insome embodiments, the substrate comprises a cutting balloon. In someembodiments, the cutting balloon comprises at least one tacking elementadapted to tack the coating to the intervention site. In someembodiments, the tacking element is adapted to secure the coating to thecutting balloon until inflation of the cutting balloon. In someembodiments, the tacking element comprises a wire. In some embodiments,the wire is shaped in the form of an outward pointing wedge. In someembodiments, the tacking element does not cut tissue at the interventionsite.

One illustration devices provided herein include a cutting balloon forthe treatment of vascular disease (e.g.; occluded lesions in thecoronary or peripheral vasculature). In this embodiment, the coating maybe preferentially located on the ‘cutting wire’ portion of the device.Upon deployment, the wire pushes into the plaque to provide the desiredtherapeutic ‘cutting’ action. During this cutting, the polymer and drugcoating is plastically deformed off of the wire by the combination ofcompressive and shear forces acting on the wire—leaving some or all ofthe coating embedded in the plaque and/or artery wall. A similarapproach may be applied to delivery of oncology drugs (a) directly totumors and/or, (b) to the arteries delivering blood to the tumors forsite-specific chemotherapy, and/or (c) to the voids left after theremoval of a tumor (lumpectomy). These oncology (as well as othernon-vascular) applications may not require the ‘cutting’ aspects andcould be provided by coatings directly onto the balloon or onto a sheathover the balloon or according to an embodiment wherein the coating formsa sheath over the deflated (pleated) balloon.

A cutting balloon embodiment described herein provides severaladvantages. Such embodiment allows for concentrating the mechanicalforce on the coating/wire as the balloon is inflated—the wire may serveto concentrate the point-of-contact-area of the balloon expansionpressure resulting in a much higher force for plastic deformation of thedrug and polymer coating vs. the non-cutting plain balloon which maydistribute the pressure over a much larger area (therefore lower forceproportional to the ratio of the areas). Embodiments involving a cuttingballoon provide for the use of polymers that would otherwise be toorigid (higher modulus) to deform from a non-cutting balloon.

Other embodiments provided herein are based on geometric configurationsof the device that optimize both the deformation and the bulk-migrationof the coating from the device. In one embodiment wherein the device isa cutting balloon, the (coated) wire of the cutting balloon is shapedlike a wedge, pointed outward.

Another embodiment provides catheter-based devices where thedrug-delivery formulation is delivered to the therapeutic site in thevasculature via inflation of a balloon.

One embodiment provides coated percutaneous devices (e.g.; balloons,whether cutting balloons or other balloon types) that, upon deploymentat a specific site in the patient, transfer some or all of thedrug-delivery formulation (5-10%, 10-25%, 25-50%, 50-90%, 90-99%,99-100%) to the site of therapeutic demand. In certain embodiments, theballoon is at least in part cylindrical as expanded or as formed. Incertain embodiments, the balloon is at least in part bulbous as expandedor as formed. In certain embodiments, the balloon is at least in partspherical as expanded or as formed. In certain embodiments, the balloonhas a complex shape as expanded or as formed (such as a double nodedshape, a triple noded shape, has a waist, and/or has an hourglass shape,for non-limiting example).

In some embodiments, transferring at least a portion of the active agentcomprises transferring at least about 3%, at least about 5%, at leastabout 10%, at least about 20%, at least about 30%, greater than 35%, atleast about 50%, at least about 75%, at least about 85%, at least about90%, at least about 95%, and/or at least about 99% of the active agentfrom the substrate. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,transferring transfers less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, at most about 35%,less than about 50%, less than about 70%, less than about 80%, and/orless than about 90% of the active agent absent stimulating at least oneof the coating and the substrate.

The term “adapted to transfer at least a portion” of the coating oractive agent to an intervention site refers to a device that is designedto transfer any portion of the coating or active agent to anintervention site.

The term “adapted to free” a portion of a coating and/or active agentfrom the substrate refers to a device, coating, and/or substrate that isdesigned to free a certain percentage of the coating and/or active agentfrom the substrate. As used herein, a device, coating, and/or substratethat is designed to free a certain percentage of the coating and/oractive agent from the substrate is designed to unrestrain the coatingand/or active agent from the substrate, and/or to remove any obstructionand/or connection the coating may have to the substrate (whether director indirect).

In some embodiments, the device is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limiting examplethe coating may be so adapted by selection of the active agent and/orthe polymer and/or the polymer-active agent composition, or by thecoating having a particular pattern—e.g. a ribbed pattern, a texturedsurface, a smooth surface, and/or another pattern, coating thickness,coating layers, and/or another physical and/or compositional attribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example the coating may be so adapted by selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute.

In some embodiments, freeing at least a portion of the coating comprisesfreeing at least about 10%, at least about 20%, at least about 30%,greater than 35%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating from the substrate. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, freeing frees less than about 1%, less than about 5%, lessthan about 10%. less than about 15%, less than about 25%, at most about35%, less than about 50%, less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulating at leastone of the coating and the substrate.

The term “adapted to dissociate” a portion of a coating and/or activeagent from the substrate refers to a device, coating, and/or substratethat is designed to dissociate a certain percentage of the coatingand/or active agent from the substrate. As used herein, a device,coating, and/or substrate that is designed to dissociate a certainpercentage of the coating and/or active agent from the substrate isdesigned to remove from association between the coating (and/or activeagent) and the substrate. Also and/or alternatively, as used herein, adevice, coating, and/or substrate that is designed to dissociate acertain percentage of the coating and/or active agent from the substrateis designed to separate the coating (and/or active agent) from thesubstrate. This separation may be reversible in some embodiments. Thisseparation may not be reversible in some embodiments.

In some embodiments, the device is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample the coating may be so adapted by selection of the active agentand/or the polymer and/or the polymer-active agent composition, or bythe coating having a particular pattern—e.g. a ribbed pattern, atextured surface, a smooth surface, and/or another pattern, coatingthickness, coating layers, and/or another physical and/or compositionalattribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate to the interventionsite. For non-limiting example the coating may be so adapted byselection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute.

In some embodiments, dissociating at least a portion of the coatingcomprises dissociating at least about 10%, at least about 20%, at leastabout 30%, greater than 35%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating from the substrate. In some embodiments,stimulating decreases the contact between the coating and the substrate.In some embodiments, dissociating dissociates less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, at most about 35%, less than about 50%, less than about 70%, lessthan about 80%, and/or less than about 90% of the coating absentstimulating at least one of the coating and the substrate.

“Plastic deformation” as used herein is the change in the physical shapeof the coating by forces induced on the device. Plastic deformationresults in increasing the contact area of the coating on the tissue anddecreasing the contact area of the coating on the device. This change incontact area results in some or all of the coating being preferentiallyexposed to the tissue instead of the device. The terms “plasticdeformation” and “plastically deform,” as used herein in the context ofa coating, are intended to include the expansion of the coating materialbeyond the elastic limit of the material such that the material ispermanently deformed. “Elastic deformation” as used herein refers to areversible alteration of the form or dimensions of the object understress or strain, e.g., inflation pressure of a balloon substrate. Theterms “plastic deformation” and “plastically deform,” as used herein inthe context of a balloon or other substrate, are intended to include theexpansion of the substrate beyond the elastic limit of the substratematerial such that the substrate material is permanently deformed. Onceplastically deformed, a material becomes substantially inelastic andgenerally will not, on its own, return to its pre-expansion size andshape. “Residual plastic deformation” refers to a deformation capable ofremaining at least partially after removal of the inflation stress,e.g., when the balloon is deflated. “Elastic deformation” as used hereinrefers to a reversible alteration of the form or dimensions of theobject (whether it is the coating or the substrate) under stress orstrain, e.g., inflation pressure.

“Shear transfer” as used herein is the force (or component of forces)orthogonal to the device that would drive the coating away from thedevice substrate. This could be induced on the device by deployment,pressure-response from the surrounding tissue and/or in-growth of tissuearound the coating.

“Bulk migration” as used herein is the incorporation of the coatingonto/into the tissue provided by the removal of the device and/orprovided by degradation of the coating over time and/or provided byhydration of the coating over time. Degradation and hydration of thecoating may reduce the coating's cohesive and adhesive binding to thedevice, thereby facilitating transfer of the coating to the tissue.

One embodiment may described by analogy to contact printing whereby abiochemically active ‘ink’ (the polymer+drug coating) from a ‘die’ (thedevice) to the ‘stock’ (the site in the body).

The devices and methods described in conjunction with some of theembodiments provided herein are advantageously based on specificproperties provided for in the drug-delivery formulation. One suchproperty, especially well-suited for non-permanent implants such asballoon catheters, cutting balloons, etc. is ‘soft’ coating thatundergoes plastic deformation at pressures provided by the inflation ofthe balloon (range 2-25 ATM, typically 10-18 ATM). Another suchproperty, especially well-suited to permanent implants such as stents iscoatings where the polymer becomes ‘soft’ at some point after implanteither by hydration or by degradation or by combinations of hydrationand degradation.

Some embodiments provide devices that can advantageously be used inconjunction with methods that can aid/promote the transfer of thecoating. These include introducing stimuli to the coated device onceon-site in the body (where the device is delivered either transiently orpermanently). Such stimuli can be provided to induce a chemical response(light, heat, radiation, etc.) in the coating or can provide mechanicalforces to augment the transfer of the coating into the tissue(ultrasound, translation, rotation, vibration and combinations thereof).

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a mechanical stimulation. In someembodiments, the coating is freed from the substrate using a mechanicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a mechanical stimulation. In some embodiments, thecoating is transferred from the substrate using a mechanicalstimulation. In some embodiments, the coating is transferred to theintervention site using a mechanical stimulation. In some embodiments,the coating is delivered to the intervention site using a mechanicalstimulation. In some embodiments, the mechanical stimulation is adaptedto augment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the mechanical stimulation isadapted to initiate the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the mechanicalstimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, themechanical stimulation comprises at least one of a compressive force, ashear force, a tensile force, a force exerted on the coating from asubstrate side of the coating, a force exerted on the coating by thesubstrate, a force exerted on the coating from an external element, atranslation, a rotation, a vibration, and a combination thereof. In someembodiments, the external element is a part of the subject. In someembodiments, the external element is not part of the device. In someembodiments, the external element comprises a liquid. In someembodiments, the liquid is forced between the coating and the substrate.In some embodiments, the liquid comprises saline. In some embodiments,the liquid comprises water. In some embodiments, the mechanicalstimulation comprises a geometric configuration of the substrate thatmaximizes a shear force on the coating. In some embodiments, themechanical stimulation comprises a geometric configuration of thesubstrate that increases a shear force on the coating. In someembodiments, the mechanical stimulation comprises a geometricconfiguration of the substrate that enhances a shear force on thecoating.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a chemical stimulation. In someembodiments, the coating is freed from the substrate using a chemicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a chemical stimulation. In some embodiments, the coatingis transferred from the substrate using a chemical stimulation. In someembodiments, the coating is transferred to the intervention site using achemical stimulation. In some embodiments, the coating is delivered tothe intervention site using a chemical stimulation. In some embodiments,the chemical stimulation comprises at least one of bulk degradation,interaction with a bodily fluid, interaction with a bodily tissue, achemical interaction with a non-bodily fluid, a chemical interactionwith a chemical, an acid-base reaction, an enzymatic reaction,hydrolysis, and combinations thereof. In some embodiments, the chemicalstimulation comprises bulk degradation of the coating. In someembodiments, the chemical stimulation comprises interaction of thecoating or a portion thereof with a bodily fluid. In some embodiments,the chemical stimulation comprises interaction of the coating or aportion thereof with a bodily tissue. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a non-bodily fluid. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a chemical. In some embodiments, the chemical stimulationcomprises an acid-base reaction. In some embodiments, the chemicalstimulation comprises an enzymatic reaction. In some embodiments, thechemical stimulation comprises hydrolysis.

In some embodiments, the chemical stimulation is adapted to augment thefreeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the chemical stimulation is adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the chemical stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the coating comprises amaterial that is adapted to transfer, free, and/or dissociate from thesubstrate when at the intervention site in response to an in-situenzymatic reaction resulting in a weak bond between the coating and thesubstrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a thermal stimulation. In someembodiments, the coating is freed from the substrate using a thermalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a thermal stimulation. In some embodiments, the coatingis transferred from the substrate using a thermal stimulation. In someembodiments, the coating is transferred to the intervention site using athermal stimulation. In some embodiments, the coating is delivered tothe intervention site using a thermal stimulation. In some embodiments,the thermal stimulation comprises at least one of a hot stimulus and acold stimulus adapted to augment the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a electromagnetic stimulation. In someembodiments, the coating is freed from the substrate using aelectromagnetic stimulation. In some embodiments, the coating isdissociated from the substrate using a electromagnetic stimulation. Insome embodiments, the coating is transferred from the substrate using aelectromagnetic stimulation. In some embodiments, the coating istransferred to the intervention site using a electromagneticstimulation. In some embodiments, the coating is delivered to theintervention site using a electromagnetic stimulation. In someembodiments, the electromagnetic stimulation comprises anelectromagnetic wave comprising at least one of a radio wave, a microwave, a infrared wave, near infrared wave, a visible light wave, anultraviolet wave, a X-ray wave, and a gamma wave. In some embodiments,the electromagnetic stimulation is adapted to augment the freeing,dissociation and/or transference of the coating from the substrate. Insome embodiments, the electromagnetic stimulation is adapted to initiatethe freeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the electromagnetic stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a sonic stimulation. In some embodiments,the coating is freed from the substrate using a sonic stimulation. Insome embodiments, the coating is dissociated from the substrate using asonic stimulation. In some embodiments, the coating is transferred fromthe substrate using a sonic stimulation. In some embodiments, thecoating is transferred to the intervention site using a sonicstimulation. In some embodiments, the coating is delivered to theintervention site using a sonic stimulation. In some embodiments, thesonic stimulation comprises a sound wave, wherein the sound wave is atleast one of an ultrasound wave, an acoustic sound wave, and aninfrasound wave. In some embodiments, the sonic stimulation is adaptedto augment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the sonic stimulation isadapted to initiate the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the sonic stimulationis adapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a combination of at least two of amechanical stimulation, a chemical stimulation, an electromagneticstimulation, and a sonic stimulation.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate by extrusion.

Provided herein are device geometries that maximize the shear forces onthe coating. Such geometric design of the device provides twoadvantages: (1) increases (concentrates) the force to plastically deformthe drug and polymer coating (2) decreases the force of adhesion of thecoating. For example, a wedge-shape aligns the forces of deformationalong a shear plan as opposed to direct compression. This embodimentprovides for: (1) increased efficiency in terms of % of the coatingtransferred (2) increased precision in amount transferred on acase-by-case basis (3) utilization of ‘harder/stiffer’ materials(biopolymers) that would otherwise not deform and/or not bulk-migrateunder deployment conditions (4) minimize the chance of particulateshedding via purposefully designing the shape and direction of both thedeformation and bulk migration. For example for a wedge, particles wouldbe less likely because the coating would be pre-disposed as a shear fromthe device in a sheet form—with the use of soft materials, this may beillustrated as a coating of silicone caulk being extruded from thepressure of a rod being pushed into a mattress.

Another embodiment provide a geometric arrangement of the coatingwhereby layers, e.g. a laminate structure, are provided in the coatingto modulate and control the plastic deformation, shearing andbulk-migration of the coating into the tissue.

One embodiment provides coated substrates that, upon deployment at aspecific site in the patient, transfer some or all of the coating(5-10%, 10-25%, 25-50%, 50-90%, 90-99%, 99-100%) to the site oftherapeutic demand.

In some embodiments, the device further comprises a release agent. Insome embodiments, the release agent is biocompatible. In someembodiments, the release agent is non-biocompatible. In someembodiments, the release agent comprises a powder. In some embodiments,the release agent comprises a lubricant. In some embodiments, therelease agent comprises a surface modification of the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid. In someembodiments, the viscous fluid is a fluid that is viscous relative tosaline. In some embodiments, the viscous fluid is a fluid that isviscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a gel.

In some embodiments, the release agent comprises at least one of theactive agent and another active agent. The active agent may be placed onthe substrate prior to the coating in order to act as the release agent.The active agent may be a different active agent than the active agentin the coating. The active agent that is the release agent may providefor a second source of drug to be delivered to the intervention site oranother location once the coating is released from (or transferred from,or freed from, or dissociated from) the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a property that iscapable of changing at the intervention site. In some embodiments, theproperty comprises a physical property. In some embodiments, theproperty comprises a chemical property. In some embodiments, the releaseagent is capable of changing a property when in contact with at leastone of a biologic tissue and a biologic fluid. In some embodiments, therelease agent is capable of changing a property when in contact with anaqueous liquid.

In some embodiments, the release agent is between the substrate and thecoating.

In some embodiments, at least a portion of the pharmaceutical agent isencapsulated using a single emulsion/evaporation technique. In someembodiments, the technique comprises at least the steps of (1) combininga first polymer (e.g. PVA) and water to form a first polymer solution;combining a second polymer (e.g. PLGA) and an organic solvent (e.g.dichloromethane) to form a second polymer solution; combining the secondpolymer (e.g. PLGA) and the organic solvent (e.g. dichloromethane) toform a third polymer solution; and combining the pharmaceutical agentand a polar aprotic solvent (e.g. DMSO) to form a pharmaceutical agentsolution, (2) mixing the second polymer solution and pharmaceuticalagent solution, (3) adding the first polymer solution and homogenizingthe resulting mixture; (4) adding the third polymer solution; (5)optionally, allowing the organic solvent to evaporate; and (6) filteringthe remaining solution. In some embodiments, the filtration isaccomplished using a centrifuge. In some embodiments, the filtration isaccomplished by passing the mixture through filter paper. In someembodiments, the encapsulated pharmaceutical agent is furtherresuspended in water and lyophilized.

In some embodiments, the polymer concentration of the first polymersolutions is from about 1% to about 10%, from about 1% to about 9%, fromabout 1% to about 8%, from about 1% to about 7%, from about 1% to about6%, from about 1% to about 5%, from about 1% to about 4%, from about 1%to about 3%, from about 1.5% to about 2.5%, or about 2%. As used herein,the term “about” when used in reference to the polymer concentrationexpressed as a percentage means a variation of 0.05%, 0.1%, 0.2%, 0.25%,0.3%, 0.4%, or 0.5%. For example a polymer concentration that is about2% may be expressed as 2%+/−0.5% (i.e. 1.5%-2.5%), or may be from1.95-2.05% (2%+/−0.05%), depending on the embodiment. In someembodiments, the polymer concentration of the first polymer solutions isfrom 1% to 10%, from 1% to 9%, from 1% to 8%, from 1% to 7%, from 1% to6%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1.5% to 2.5%, or2%.

In some embodiments, the polymer concentration of the second polymersolution is from about 10 mg/mL to about 100 mg/mL, from about 15 mg/mLto about 95 mg/mL. from about 20 mg/mL to about 90 mg/mL, from about 25mg/mL to about 85 mg/mL, from about 30 mg/mL to about 80 mg/mL, fromabout 35 mg/mL to about 75 mg/mL, from about 40 mg/mL to about 70 mg/mL,from about 40 mg/mL to about 60 mg/mL, from about 45 mg/mL to about 55mg/mL, or about 50 mg/mL. As used herein, the term “about” when used inreference to the polymer concentration expressed in mg/mL means avariation of 1 mg/mL, 5 mg/mL, 10 mg/mL, or 15 mg/mL, depending on theembodiment. In some embodiments, the polymer concentration of the secondpolymer solution is from 10 mg/mL to 100 mg/mL, from 15 mg/mL to 95mg/mL. from 20 mg/mL to 90 mg/mL, bet from ween 25 mg/mL to 85 mg/mL,from 30 mg/mL to 80 mg/mL, from 35 mg/mL to 75 mg/mL, from 40 mg/mL to70 mg/mL, from 40 mg/mL to 60 mg/mL, from 45 mg/mL to 55 mg/mL, or 50mg/mL

In some embodiments, the polymer concentration of the third polymersolutions is from about 0.5% to about 5%, from about 0.5% to about 4.5%,from about 0.5% to about 4%, from about 0.5% to about 3.5%, from about0.5% to about 3%, from about 0.5% to about 2.5%, from about 0.5% toabout 2%, from about 0.5% to about 1.5%, or about 2%. As used herein,the term “about” when used in reference to the polymer concentrationexpressed as a percentage means a variation of 0.05%, 0.1%, 0.2%, 0.25%,0.3%, 0.4%, or 0.5%. For example a polymer concentration that is about2% may be expressed as 2%+/−0.5% (i.e. 1.5%-2.5%), or may be from1.95-2.05% (2%+/−0.05%), depending on the embodiment. In someembodiments, the polymer concentration of the third polymer solutions isfrom 0.5% to 5%, from 0.5% to 4.5%, from 0.5% to 4%, from 0.5% to 3.5%,from 0.5% to 3%, from 0.5% to 2.5%, from 0.5% to 2%, from 0.5% to 1.5%,or 2%.

In some embodiments, the concentration of the pharmaceutical agent inthe pharmaceutical agent solution is from about 1 mg/mL to about 50mg/mL, from about 1 mg/mL to about 40 mg/mL. from about 1 mg/mL to about30 mg/mL, from about 2 mg/mL to about 30 mg/mL, from about 5 mg/mL toabout 30 mg/mL, from about 5 mg/mL to about 25 mg/mL, from about 5 mg/mLto about 20 mg/mL, from about 5 mg/mL to about 15 mg/mL, from about 7mg/mL to about 12 mg/mL, or about 10 mg/mL. As used herein, the term“about” when used in reference to the polymer concentration expressed inmg/mL means a variation of 0.5 mg/mL, 1 mg/mL, 5 mg/mL, 10 mg/mL, or 15mg/mL, depending on the embodiment. In some embodiments, theconcentration of the pharmaceutical agent in the pharmaceutical agentsolution is from 1 mg/mL to 50 mg/mL, between 1 mg/mL to 40 mg/mL. from1 mg/mL to 30 mg/mL, from 2 mg/mL to 30 mg/mL, from 5 mg/mL to 30 mg/mL,from 5 mg/mL to 25 mg/mL, from 5 mg/mL to 20 mg/mL, from 5 mg/mL to 15mg/mL, from 7 mg/mL to 12 mg/mL, or 10 mg/mL.

In some embodiments, the volume of the organic solvent removed byevaporation is at least 5%, at least 10%, at least 15%, at least 20%, atleast 30%, at least 40%, at least 45%, at least 50%, at least, 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, or at least 95%. In some embodiments, thevolume of the organic solvent removed by evaporation is 5%-95%, at5%-85%, 5%-50%, 5%-25%, 5%-10%, 10%-95%, 10%-50%, 10%-30%, 20%-95%,30%-75%, 40%-95%, 50%-95%, 70%-90%, 75%-95%, or 80%-95%.

In some embodiment, a crystalline pharmaceutical agent can beencapsulated by emulsion-based encapsulation processes. In someembodiments, at least a portion of the pharmaceutical agent isencapsulated using a technique that comprises at least the steps of (1)combining a first polymer (e.g. PVA) and water to form a first polymersolution, combining a second polymer (e.g. PLGA) and an organic solvent(e.g. dichloromethane) to form a second polymer solution, and combiningthe second polymer and the organic solvent to form a third polymersolution; (2) mixing the first and second polymer solutions and allowingthe organic solvent to evaporate to form an emulsion; (3) mixing thepharmaceutical agent to the third polymer solution to form a suspension;(4) combining the emulsion and suspension to form an emulsion-basedmixture; and (5) filtering the emulsion-based mixture. In someembodiments, the filtration is accomplished using a centrifuge. In someembodiments the filtration is accomplished by pouring the solutionthrough filter paper. In some embodiments, the encapsulatedpharmaceutical agent is further resuspended in water and lyophilized.

In some embodiments, the polymer concentration of the first polymersolutions is from about 1% to about 10%, from about 1% to about 9%, fromabout 1% to about 8%, from about 1% to about 7%, from about 1% to about6%, from about 1% to about 5%, from about 1% to about 4%, from about 1%to about 3%, from about 1.5% to about 2.5%, or about 2%. As used herein,the term “about” when used in reference to the polymer concentrationexpressed as a percentage means a variation of 0.05%, 0.1%, 0.15%, 0.2%,0.3%, 0.4%, or 0.5%. For example a polymer concentration that is about2% may be expressed as 2%+/−0.5% (i.e. 1.5%-2.5%), or may be from1.95-2.05% (2%+/−0.05%), depending on the embodiment. In someembodiments, the polymer concentration of the first polymer solutions isfrom 1% to 10%, from 1% to 9%, from 1% to 8%, from 1% to 7%, from 1% to6%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1.5% to 2.5%, or2%.

In some embodiments, the polymer concentration of the second polymersolution is from about 10 mg/mL to about 100 mg/mL, from about 15 mg/mLto about 95 mg/mL. from about 20 mg/mL to about 90 mg/mL, from about 25mg/mL to about 85 mg/mL, from about 30 mg/mL to about 80 mg/mL, fromabout 35 mg/mL to about 75 mg/mL, from about 40 mg/mL to about 70 mg/mL,from about 40 mg/mL to about 60 mg/mL, from about 45 mg/mL to about 55mg/mL, or about 50 mg/mL. As used herein, the term “about” when used inreference to the polymer concentration expressed in mg/mL means avariation of 0.5 mg/mL, 1 mg/mL, 5 mg/mL, 10 mg/mL, or 15 mg/mL,depending on the embodiment. In some embodiments, the polymerconcentration of the second polymer solution is from 10 mg/mL to 100mg/mL, from 15 mg/mL to 95 mg/mL. from 20 mg/mL to 90 mg/mL, from 25mg/mL to 85 mg/mL, from 30 mg/mL to 80 mg/mL, from 35 mg/mL to 75 mg/mL,from 40 mg/mL to 70 mg/mL, from 40 mg/mL to 60 mg/mL, from 45 mg/mL to55 mg/mL, or 50 mg/mL.

In some embodiments, the polymer concentration of the third polymersolutions is from about 0.5% to about 5%, from about 0.5% to about 4.5%,from about 0.5% to about 4%, from about 0.5% to about 3.5%, from about0.5% to about 3%, from about 0.5% to about 2.5%, from about 0.5% toabout 2%, from about 0.5% to about 1.5%, or about 2%. As used herein,the term “about” when used in reference to the polymer concentrationexpressed as a percentage means a variation of 0.05%, 0.1%, 0.15%, 0.2%,0.3%, 0.4%, or 0.5%. For example a polymer concentration that is about2% may be expressed as 2%+/−0.5% (i.e. 1.5%-2.5%), or may be from1.95-2.05% (2%+/−0.05%), depending on the embodiment. In someembodiments, the polymer concentration of the third polymer solutions isfrom 0.5% to 5%, from 0.5% to 4.5%, from 0.5% to 4%, from 0.5% to 3.5%,from 0.5% to 3%, from 0.5% to 2.5%, from 0.5% to 2%, from 0.5% to 1.5%,or 2%.

In some embodiments, the concentration of the pharmaceutical agent inthe pharmaceutical agent-third polymer solution mixture is from about0.01 mg/mL to about 0.1 mg/mL, from about 0.02 mg/mL to about 0.09mg/mL. from about 0.03 mg/mL to about 0.08 mg/mL, from about 0.03 mg/mLto about 0.07 mg/mL, from about 0.04 mg/mL to about 0.07 mg/mL, fromabout 0.04 mg/mL to about 0.06 mg/mL, or about 0.05 mg/mL. As usedherein, the term “about” when used in reference to the pharmaceuticalagent concentration expressed in mg/mL means a variation of 0.001 mg/mL,0.005 mg/mL, 5 mg/mL, 0.002 mg/mL, 0.0025 mg/mL, or 0.1 mg/mL, dependingon the embodiment. In some embodiments, the concentration of thepharmaceutical agent in the pharmaceutical agent-third polymer solutionmixture is from 0.01 mg/mL to 0.1 mg/mL, from 0.02 mg/mL to 0.09 mg/m,from about 0.03 mg/mL to 0.08 mg/mL, from about 0.03 mg/mL to 0.07mg/mL, from about 0.04 mg/mL to about 0.07 mg/mL, from about 0.04 mg/mLto about 0.06 mg/mL, or about 0.05 mg/mL.

In some embodiments, the volume of the organic solvent removed byevaporation during the encapsulation process is at least 5%, at least10%, at least 15%, at least 20%, at least 30%, at least 40%, at least45%, at least 50%, at least, 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, and atleast 95%. In some embodiments, the volume of the organic solventremoved by evaporation during the encapsulation process is 5%-95%, at5%-85%, 5%-50%, 5%-25%, 5%-10%, 10%-95%, 10%-50%, 10%-30%, 20%-95%,30%-75%, 40%-95%, 50%-95%, 70%-90%, 75%-95%, or 80%-95%.

In some embodiment, the polymer-encapsulated pharmaceutical agent is inthe form of microspheres or microparticles. Examples of microspheresrelevant to the present disclosure include: Luzzi, L. A., J. Pharm. Psy.59:1367 (1970); U.S. Pat. No. 4,530,840; Lewis, D. H., “ControlledRelease of Bioactive Agents from Lactides/Glycolide Polymers” inBiodegradable Polymers as Drug Delivery Systems, Chasin, M. and Langer,R., eds., Marcel Decker (1990); U.S. Pat. No. 4,675,189; Beck et al.,“Poly(lactic acid) and Poly(lactic acid-co-glycolic acid) ContraceptiveDelivery Systems,” in Long Acting Steroid Contraception, Mishell, D. R.,ed., Raven Press (1983); U.S. Pat. No. 4,758,435; U.S. Pat. No.3,773,919; U.S. Pat. No. 4,474,572. Examples of protein therapeuticsformulated as microspheres include: U.S. Pat. No. 6,458,387; U.S. Pat.No. 6,268,053; U.S. Pat. No. 6,090,925; U.S. Pat. No. 5,981,719; andU.S. Pat. No. 5,578,709, and are herein incorporated by reference forsuch disclosure.

Microspheres usually have a spherical shape, although irregularly-shapedmicroparticles are possible. Microspheres may vary in size, ranging fromsubmicron to 1000 micron diameters. Microspheres suitable for use withthe medical device coating disclosed herein are submicron to 250 microndiameter microspheres. The microspheres are prepared by any method whichproduces microspheres in a size range acceptable for use in the coatingmethod disclosed herein.

Suitable examples of polymeric materials for use in the microsphere ormicroparticles herein include poly(glycolic acid), poly-d,l-lactic acid,poly-l-lactic acid, copolymers of the foregoing, poly(aliphaticcarboxylic acids), copolyoxalates, polycaprolactone, polydioxonene,poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone),polyorthoesters, poly(glycolic acid-caprolactone), polydioxonene,polyanhydrides, polyphosphazines, and natural polymers includingalbumin, casein, and some waxes, such as, glycerol mono- and distearate,and the like. Various commercially available poly(lactide-co-glycolide)materials (PLGA) are optionally used in the method disclosed herein. Forexample, poly(d,l-lactic-co-glycolic acid) is commercially availablefrom Boehringer-Ingelheim as RESOMER RG 503 H. This product has a molepercent composition of 50% lactide and 50% glycolide. These copolymersare available in a wide range of molecular weights and ratios of lacticacid to glycolic acid. One embodiment includes the use of the polymerpoly(d,l-lactide-co-glycolide). The molar ratio of lactide to glycolidein such a copolymer includes the range of from about 95:5 to about50:50.

The molecular weight of the polymeric material is of some importance. Insome embodiment, the molecular weight is high enough so that it formssatisfactory polymer coatings, i.e., the polymer should be a good filmformer. Usually, a satisfactory molecular weight is in the range of5,000 to 500,000 daltons. The molecular weight of a polymer is alsoimportant from the point of view that molecular weight influences thebiodegradation rate of the polymer. The pharmaceutical agent is releasedfrom the microparticles through diffusional through the polymermaterial, through biodegradation of the polymer material, or through acombination of both. By an appropriate selection of polymeric materialsa microsphere formulation is made such that the resulting microspheresexhibit both diffusional release and biodegradation release properties.This is useful in affording multiphasic release patterns.

A variety of methods are known by which compounds are encapsulated inmicrospheres. In these methods, the pharmaceutical agent is generallydispersed or emulsified, using stirrers, agitators, or other dynamicmixing techniques, in a solvent containing a wall-forming material.Solvent is then removed from the microspheres, and thereafter themicrosphere product is obtained.

In one embodiment, the polymer-encapsulated pharmaceutical agent usedherein are made through the incorporation of the pharmaceutical agentsand/or other pharmaceutical agents into poly(lactic-glycolicacid)-polyvinyl alcohol microspheres. In another embodiment, the aurissensory cell modulating agents are encapsulated into alginatemicrospheres. (See U.S. Pat. No. 6,036,978, incorporated herein for suchdisclosure). Biocompatible methacrylate-based polymers to encapsulatethe pharmaceutical agent are optionally used in the formulations andmethods disclosed herein. A wide range of methacrylate-based polymersystems are commercially available, such as the EUDRAGIT polymersmarketed by Evonik. One useful aspect of methacrylate polymers is thatthe properties of the formulation are varied by incorporating variousco-polymers. For example, poly(acrylic acid-co-methylmethacrylate)microparticles exhibit enhanced mucoadhesion properties as thecarboxylic acid groups in the poly(acrylic acid) form hydrogen bondswith mucin (Park et al, Pharm. Res. (1987) 4(6):457-464). Variation ofthe ratio between acrylic acid and methylmethacrylate monomers serves tomodulate the properties of the co-polymer. Methacrylate-basedmicroparticles have also been used in protein therapeutic formulations(Naha et al, Journal of Microencapsulation 4 February, 2008 (onlinepublication)).

An example of a conventional microencapsulation process forpharmaceutical preparations is shown in U.S. Pat. No. 3,737,337,incorporated herein by reference for such disclosure. The pharmaceuticalagent to be encapsulated or embedded are dissolved or dispersed in theorganic solution of the polymer (phase A), using conventional mixers,including (in the preparation of dispersion) vibrators and high-speedstirrers, etc. The dispersion of phase (A), containing the core materialin solution or in suspension, is carried out in the aqueous phase (B),again using conventional mixers, such as high-speed mixers, vibrationmixers, or even spray nozzles, in which case the particle size of themicrospheres will be determined not only by the concentration of phase(A), but also by the emulsate or microsphere size. With conventionaltechniques for the microencapsulation of auris sensory cell modulatingagents, the microspheres form when the solvent containing an activeagent and a polymer is emulsified or dispersed in an immiscible solutionby stirring, agitating, vibrating, or some other dynamic mixingtechnique.

Methods for the construction of microspheres are also described in U.S.Pat. No. 4,389,330, and U.S. Pat. No. 4,530,840, incorporated herein byreference for such disclosure. The pharmaceutical agent is dissolved ordispersed in an appropriate solvent. To the agent-containing medium isadded the polymeric matrix material in an amount relative to the activeingredient which gives a product of the desired loading of active agent.Optionally, all of the ingredients of the auris sensory cell modulatingagent microsphere product can be blended in the solvent medium together.Suitable solvents for the agent and the polymeric matrix materialinclude organic solvents such as acetone, halogenated hydrocarbons suchas chloroform, methylene chloride and the like, aromatic hydrocarboncompounds, halogenated aromatic hydrocarbon compounds, cyclic ethers,alcohols, ethyl acetate and the like.

The mixture of ingredients in the solvent is emulsified in acontinuous-phase processing medium; the continuous-phase medium beingsuch that a dispersion of microdroplets containing the indicatedingredients is formed in the continuous-phase medium. Naturally, thecontinuous-phase processing medium and the organic solvent must beimmiscible, and includes water although nonaqueous media such as xyleneand toluene and synthetic oils and natural oils are optionally used.Optionally, a surfactant is added to the continuous-phase processingmedium to prevent the microparticles from agglomerating and to controlthe size of the solvent microdroplets in the emulsion. A preferredsurfactant-dispersing medium combination is a 1 to 10 wt. % poly(vinylalcohol) in water mixture. The dispersion is formed by mechanicalagitation of the mixed materials. An emulsion is optionally formed byadding small drops of the active agent-wall forming material solution tothe continuous phase processing medium. The temperature during theformation of the emulsion is not especially critical but influences thesize and quality of the microspheres and the solubility of the drug inthe continuous phase. It is desirable to have as little of the agent inthe continuous phase as possible. Moreover, depending on the solvent andcontinuous-phase processing medium employed, the temperature must not betoo low or the solvent and processing medium will solidify or theprocessing medium will become too viscous for practical purposes, or toohigh that the processing medium will evaporate, or that the liquidprocessing medium will not be maintained. Moreover, the temperature ofthe medium cannot be so high that the stability of the particular agentbeing incorporated in the microspheres is adversely affected.Accordingly, the dispersion process is conducted at any temperaturewhich maintains stable operating conditions, which preferred temperaturebeing about 15° C. to 60° C., depending upon the drug and excipientselected.

The dispersion which is formed is a stable emulsion and from thisdispersion the organic solvent immiscible fluid is optionally partiallyremoved in the first step of the solvent removal process. The solvent isremoved by techniques such as through evaporation, heating, theapplication of a reduced pressure or a combination of both. Thetemperature employed to evaporate solvent from the microdropletsgenerally should not degrade the pharmaceutical agent employed in thepreparation of a given microparticle, nor should it be so high as toevaporate solvent at such a rapid rate to cause defects in the wallforming material. Generally, from 5 to 95%, of the solvent is removed inthe first solvent removal step.

After the first stage, the dispersed microparticles in the solventimmiscible fluid medium are isolated from the fluid medium by anyconvenient means of separation. Thus, for example, the fluid is decantedfrom the microsphere or the microsphere suspension is filtered. Stillother, various combinations of separation techniques are used ifdesired.

Following the isolation of the microspheres from the continuous-phaseprocessing medium, the remainder of the solvent in the microspheres isremoved by optional extraction. In this step, the microspheres aresuspended in the same continuous-phase processing medium used in stepone, with or without surfactant, or in another liquid. The extractionmedium removes the solvent from the microspheres and yet does notdissolve the microspheres. During the extraction, the extraction mediumwith dissolved solvent is optionally removed and replaced with freshextraction medium. This is best done on a continual basis. The rate ofextraction medium replenishment of a given process is a variable whichis determined at the time the process is performed and, therefore, noprecise limits for the rate must be predetermined After the majority ofthe solvent has been removed from the microspheres, the microspheres aredried by exposure to air or by other conventional drying techniques suchas vacuum drying, drying over a desiccant, or the like. This process isvery efficient in encapsulating the auris sensory cell modulating agentsince core loadings of up to 80 wt. %, preferably up to 60 wt. % areobtained.

Methods of Manufacturing Generally

In some embodiments, a coating is formed on the substrate by a processcomprising depositing a polymer and/or the active agent by an e-RESS, ane-SEDS, or an e-DPC process. In some embodiments, the process of formingthe coating provides improved adherence of the coating to the substrateprior to deployment of the device at the intervention site andfacilitates dissociation of the coating from the substrate at theintervention site. In some embodiments, the coating is formed on thesubstrate by a process comprising depositing the active agent by ane-RESS, an e-SEDS, or an e-DPC process without electrically charging thesubstrate. In some embodiments, the coating is formed on the substrateby a process comprising depositing the active agent on the substrate byan e-RESS, an e-SEDS, or an e-DPC process without creating an electricalpotential between the substrate and a coating apparatus used to depositthe active agent.

Means for creating the bioabsorbable polymer(s)+drug (s) coating of thedevice with or without a substrate:

-   -   Spray coat the coating-form with drug and polymer as is done in        Micell process (e-RESS, e-DPC, compressed-gas sintering).    -   Perform multiple and sequential coating-sintering steps where        different materials may be deposited in each step, thus creating        a laminated structure with a multitude of thin layers of        drug(s), polymer(s) or drug+polymer that build the final device.    -   Perform the deposition of polymer(s)+drug(s) laminates with the        inclusion of a mask on the inner (luminal) surface of the        device. Such a mask could be as simple as a non-conductive        mandrel inserted through the internal diameter of the coating        form. This masking could take place prior to any layers being        added, or be purposefully inserted after several layers are        deposited continuously around the entire coating-form.

In some embodiments, the coating comprises a microstructure. In someembodiments, particles of the active agent are sequestered orencapsulated within the microstructure. In some embodiments, themicrostructure comprises microchannels, micropores and/or microcavities.In some embodiments, the microstructure is selected to allow sustainedrelease of the active agent. In some embodiments, the microstructure isselected to allow controlled release of the active agent.

Other methods for preparing the coating include solvent based coatingmethods and plasma based coating methods. In some embodiments, thecoating is prepared by a solvent based coating method. In someembodiments, the coating is prepared by a solvent plasma based coatingmethod.

Another advantage of the present invention is the ability to create adelivery device with a controlled (dialed-in) drug-elution profile. Viathe ability to have different materials in each layer of the laminatestructure and the ability to control the location of drug(s)independently in these layers, the method enables a device that couldrelease drugs at very specific elution profiles, programmed sequentialand/or parallel elution profiles. Also, the present invention allowscontrolled elution of one drug without affecting the elution of a seconddrug (or different doses of the same drug).

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted totransfer from the substrate to an intervention site upon stimulating thecoating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without electricallycharging the substrate, wherein forming the coating results in at leasta portion of the coating being adapted to transfer from the substrate toan intervention site upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without creating anelectrical potential between the substrate and a coating apparatus usedin the at least one e-RESS, an e-SEDS, and an e-DPC process, whereinforming the coating results in at least a portion of the coating beingadapted to transfer from the substrate to an intervention site uponstimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to transferfrom the substrate to an intervention site upon stimulating the coatingwith a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted tofree from the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to free fromthe substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todissociate from the substrate upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to dissociatefrom the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todeliver to the intervention site upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to deliver tothe intervention site upon stimulating the coating with a stimulation.

In some embodiments, the e-RESS, the e-SEDS, and/or the e-DPC processused in forming the coating is performed without electrically chargingthe substrate. In some embodiments, the e-RESS, the e-SEDS, and/or thee-DPC process used in forming the coating is performed without creatingan electrical potential between the substrate and the coating apparatusused in the e-RESS, the e-SEDS, and/or the e-DPC process.

In some embodiments, forming the coating results in the coating adheringto the substrate prior to the substrate reaching the intervention site.

Some embodiments further comprise providing a release agent on thesubstrate. In some embodiments, providing the release agent step isperformed prior to the forming the coating step. In some embodiments,the release agent comprises at least one of: a biocompatible releaseagent, a non-biocompatible release agent, a powder, a lubricant, asurface modification of the substrate, a viscous fluid, a gel, theactive agent, a second active agent, a physical characteristic of thesubstrate. In some embodiments, the physical characteristic of thesubstrate comprises at least one of: a patterned coating surface of thesubstrate, and a ribbed surface of the substrate. In some embodiments,the release agent comprises a property that is capable of changing atthe intervention site. In some embodiments, the property comprises aphysical property. In some embodiments, the property comprises achemical property. In some embodiments, the release agent is capable ofchanging a property when in contact with at least one of a biologictissue and a biologic fluid. In some embodiments, the release agent iscapable of changing a property when in contact with an aqueous liquid.In some embodiments, the coating results in a coating property thatfacilitates transfer of the coating to the intervention site. In someembodiments, the coating property comprises a physical characteristic ofthe coating. In some embodiments, the physical characteristic comprisesa pattern.

In some embodiments, forming the coating facilitates transfer of thecoating to the intervention site.

In some embodiments, transferring, freeing, dissociating, depositing,and/or tacking step comprises softening the polymer by hydration,degradation or by a combination of hydration and degradation. In someembodiments, the transferring, freeing, dissociating, depositing, and/ortacking step comprises softening the polymer by hydrolysis of thepolymer.

In some embodiments, the providing step comprises forming the coating bya solvent based coating method. In some embodiments, the providing stepcomprises forming the coating by a solvent plasma based method.

In some embodiments, providing the device comprises depositing aplurality of layers on the substrate to form the coating, wherein atleast one of the layers comprises the active agent. In some embodiments,at least one of the layers comprises a polymer. In some embodiments, thepolymer is bioabsorbable. In some embodiments, the active agent and thepolymer are in the same layer, in separate layers, or form overlappinglayers. In some embodiments, the plurality of layers comprise fivelayers deposited as follows: a first polymer layer, a first active agentlayer, a second polymer layer, a second active agent layer and a thirdpolymer layer.

EXAMPLES

The following examples are provided to illustrate selected embodiments.They should not be considered as limiting the scope of the invention,but merely as being illustrative and representative thereof. For eachexample listed herein, multiple analytical techniques may be provided.Any single technique of the multiple techniques listed may be sufficientto indicate the parameter and/or characteristic being tested, or anycombination of techniques may be used to indicate such parameter and/orcharacteristic. Those skilled in the art will be familiar with a widerange of analytical techniques for the characterization of drug/polymercoatings. Techniques presented here, but not limited to, may be used toadditionally and/or alternatively characterize specific properties ofthe coatings with variations and adjustments employed which would beobvious to those skilled in the art.

Sample Preparation

Generally speaking, coatings on stents, on balloons, on coupons, onother substrates, or on samples prepared for in-vivo models are preparedas herein. Nevertheless, modifications for a given analytical method arepresented within the examples described, and/or would be obvious to onehaving skill in the art. Thus, numerous variations, changes, andsubstitutions will now occur to those skilled in the art withoutdeparting from the invention. It should be understood that variousalternatives to the embodiments of the invention described herein andexamples provided may be employed in practicing the invention andindicating the parameters and/or characteristics described.

Coatings on Balloons

Coated balloons as described herein and/or made by a method disclosedherein are prepared. In some examples, the coated balloons have atargeted coating thickness of ˜15 microns (˜5 microns of active agent).In some examples, the coating process is PDPDP (Polymer, sinter, Drug,Polymer, sinter, Drug, Polymer, sinter) using deposition of drug in drypowder form and deposition of polymer particles by RESS methods andequipment described herein. In the illustrations herein, resultingcoated balloons may have a 3-layer coating comprising polymer (forexample, PLGA) in the first layer, drug (for example, rapamycin) in asecond layer and polymer in the third layer, where a portion of thethird layer is substantially drug free (e.g. a sub-layer within thethird layer having a thickness equal to a fraction of the thickness ofthe third layer). As described layer, the middle layer (or drug layer)may be overlapping with one or both first (polymer) and third (polymer)layer. The overlap between the drug layer and the polymer layers isdefined by extension of polymer material into physical space largelyoccupied by the drug. The overlap between the drug and polymer layersmay relate to partial packing of the drug particles during the formationof the drug layer. When crystal drug particles are deposited on top ofthe first polymer layer, voids and or gaps may remain between drycrystal particles. The voids and gaps are available to be occupied byparticles deposited during the formation of the third (polymer) layer.Some of the particles from the third (polymer) layer may rest in thevicinity of drug particles in the second (drug) layer. When thesintering step is completed for the third (polymer) layer, the thirdpolymer layer particles fuse to form a continuous film that forms thethird (polymer) layer. In some embodiments, the third (polymer) layerhowever will have a portion along the longitudinal axis of the stentwhereby the portion is free of contacts between polymer material anddrug particles. The portion of the third layer that is substantially ofcontact with drug particles can be as thin as 1 nanometer.

Polymer-coated balloons having coatings comprising polymer but no drugare made by a method disclosed herein and are prepared having a targetedcoating thickness of, for example, about 0.5, 1, 2, 3, 4, 5, 10, 15, 20,25, 30, 35, 40, 45, or 50 microns, depending in part on whether thecoating expands upon hydration and if so whether it is hydrated. Inembodiments, the coating thickness is 1-5 microns. In other embodiments,it is 1-10 microns.

An example coating process is PPP (PLGA, sinter, PLGA, sinter, PLGA,sinter) using RESS methods and equipment described herein. Thesepolymer-coated balloons may be used as control samples in some of theexamples, infra.

In some examples, the balloons are made of a compliant polymer. In someexamples, the balloons are made of a non-compliant polymer. The balloonsmay be, in some examples, 5 to 50 mm in length, preferably 10-20 mm inlength.

Balloons can be coated while inflated, and later compacted, or they canbe coated while uninflated. If a balloon is coated while inflated andlater folded or otherwise compacted, then a portion of the coating canbe protected during insertion by virtue of being disposed within theportion of the balloon that is not exposed until inflation. The coatingcan also be protected by using a sheath or other covering, as describedin the art for facilitating insertion of an angioplasty balloon.

The coating released from a balloon may be analyzed (for example, foranalysis of a coating band and/or coating a portion of the balloon).Alternatively, in some examples, the coating is analyzed directly on theballoon. This coating, and/or coating and balloon, may be sliced intosections which may be turned 90 degrees and visualized using the surfacecomposition techniques presented herein or other techniques known in theart for surface composition analysis (or other characteristics, such ascrystallinity, for example). In this way, what could be an analysis ofcoating composition through a depth when the coating is on the balloonor as removed from the balloon (i.e. a depth from the abluminal surfaceof the coating to the surface of the removed coating that once contactedthe balloon or a portion thereof), becomes a surface analysis of thecoating which can, for example, indicate the layers in the slice ofcoating, at much higher resolution. Residual coating on an extractedballoon also can be analyzed and compared to the amount of coating on anunused balloon, using, e.g., HPLC, as noted herein. Coating removed fromthe balloon, or analyzed without removal and/or release from theballoon, may be treated the same way, and assayed, visualized, and/orcharacterized as presented herein using the techniques described and/orother techniques known to a person of skill in the art.

Sample Preparation for In-Vivo Models

Devices comprising balloons having coatings disclosed herein aredeployed in the porcine coronary arteries of pigs (domestic swine,juvenile farm pigs, or Yucatan miniature swine). Porcine coronaryangioplasty is exploited herein since such model yields results that arecomparable to other investigations assaying neointimal hyperplasia inhuman subjects. The balloons are expanded to a 1:1.1 balloon:arteryratio. At multiple time points, animals are euthanized (e.g. t=1 day, 7days, 14 days, 21 days, and 28 days), the tissue surrounding theintervention site is extracted, and assayed.

Devices comprising balloons having coatings disclosed hereinalternatively are implanted in the common iliac arteries of New Zealandwhite rabbits. The balloons are expanded to a 1:1.1 balloon:arteryratio. At multiple time points, animals are euthanized (e.g., t=1 day, 7days, 14 days, 21 days, and 28 days), the tissue surrounding theintervention site is extracted, and assayed.

Example 1 Cutting Balloons

Cutting Balloon (1)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. Upon deflation and removal of the cutting balloon from theintervention site, at least about 5% to at least about 30% of thecoating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50% of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 1 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of ˜2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 1 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate˜1-2months) and sirolimus with total loading of sirolimus˜20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. A serum sample as well as a tissuesample from the deployment site is collected.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to indicate improvementand/or treatment of a disease and/or ailment, for example, by testinghigh sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-1β (IL-1β) and/or monocyte chemoattractant protein-1(MCP-1). The release kinetics of the drug may be indicated by plottingthe sirolimus concentrations at the timepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (2)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated using a solution-based system (spray or dipcoating) comprising a polymer and an active agent. The coated cuttingballoon is positioned at the intervention site. The balloon is inflatedto at least 25% below its nominal inflation pressure. At least about 5%to at least about 30% of the coating is freed from the surface of thecutting balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process using a sprayand/or dip coating process is employed. The intervention site is avascular lumen wall. Upon inflation of the cutting balloon, at leastabout 50% of the coating is freed from the device at the interventionsite.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and coatingprocess using a spray and/or dip coating process is employed. Theintervention site is a coronary artery. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processusing a spray and/or dip coating process is employed. The interventionsite is a cavity resulting from removal of a tumor. Upon inflation ofthe cutting balloon, at least about 75% of the coating is transferredfrom the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate˜1-2months) and sirolimus with total loading of sirolimus˜20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to indicate improvementand/or treatment of a disease and/or ailment, for example, by testinghigh sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-1β (IL-1β) and/or monocyte chemoattractant protein-1(MCP-1). The release kinetics of the drug may be indicated by plottingthe sirolimus concentrations at the timepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inusing spray and/or dip coating process is secured to a balloon catheter.A segment of optically clear TYGON® B-44-3 tubing with O.D.=0.125″,I.D.=0.0625″ (Available from McMaster-Carr Part Number: 5114K11(www.mcmaster.com)) is filled with phosphate-buffered saline solutionand immersed in a water bath at 37° C. to mimic physiological conditionsof deployment into a subject. The coated balloon is inserted into thetubing and the balloon is inflated to at least 25% below the balloon'snominal pressure to mechanically transfer the coating from the balloonto the tubing wall. The balloon is deflated and removed from the tubing.Optical microscopy is performed on the tubing and/or the balloon (whichis inflated to at least 25% below the balloon's nominal pressure, atleast) to determine the presence and amount of coating transferred tothe tubing and/or the amount of coating freed, dissociated, and/ortransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (3)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a release agent, a polymer and anactive agent. The coated cutting balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. At least about 5% to at least about 50% ofthe coating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example2 is employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50% of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 2 is employed. The intervention site is a coronaryartery. The release agent is ePTFE powder. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 2 is employed. The release agent a micronized activeagent or another active agent in a micronized form. The interventionsite is a cavity resulting from removal of a tumor. Upon inflation ofthe cutting balloon, at least about 75% of the coating is transferredfrom the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate˜1-2months) and sirolimus with total loading of sirolimus˜20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. The tissue and serum samples may besubjected to analysis for sirolimus concentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is an angioplasty catheter and the substrate is theballoon of the catheter) may be used to determine the percent of coatingfreed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β) and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe indicated by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 2 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingtransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (4)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. At least about 10% to at least about 50% of the coating isfreed from the surface of the cutting balloon and is deposited at theintervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example3 is employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50% of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 3 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of ˜2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 3 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate˜1-2months) and sirolimus with total loading of sirolimus˜20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is acutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β) and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe indicated by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 3 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (5)—Mechanical and Chemical Stimulation to Free theCoating

A cutting balloon is coated with a formulation comprising a base layerof methyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+paclitaxel with total dose of paclitaxel approx. 0.5 μg/mm2 of thewire. The coating and sintering process is similar to that as describedin Example 1. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The coated cuttingballoon is positioned at the intervention site. The balloon ispressurized to at least to at least 25% below its nominal inflationpressure. Upon pressurization of the cutting balloon in the diseasedartery, at least about 10% to at least about 30% of the coating isreleased into the intervention site and upon depressurization andremoval of the device, this material is deposited at the interventionsite.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon.

In one example, a base layer of methyl acrylate-methacrylic acidcopolymer is formed and additional layers of the coating is about 50:50PLGA-Ester End Group, MW˜19 kD, degradation rate˜1-2 months or about50:50 PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days.The active agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The intervention site isa vascular lumen wall. Upon inflation of the cutting balloon, at leastabout 50% of the coating is freed from the device at the interventionsite.

In another example, a cutting balloon is coated with a base layer ofmethyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+sirolimus with total loading of sirolimus˜20μ. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. The balloon is constructed of a semipermable polymer.The pressurization medium is pH 8 phosphate buffer. Upon inflation ofthe cutting balloon, about 5% to about 15% of the coating is freed fromthe device resulting in delivery of ˜2.0 μg of drug delivered to theartery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 1 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate˜1-2months) and sirolimus with total loading of sirolimus˜20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is ancutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β) and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe indicated by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Example 2 Drug-Delivery Balloon Catheters

Drug-Delivery Balloon (1)—Compliant Balloon

A compliant balloon is coated with a material comprising a polymer andan active agent. The coated compliant balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of the compliantballoon from the intervention site, at least about 5% to at least about30% of the coating is freed from the surface of the compliant balloonand is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The intervention site is a vascular lumen wall. Uponinflation of the compliant balloon, at least about 50% of the coating isfreed from the device at the intervention site.

In another example, a compliant balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus˜20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the compliant balloon, about 5% toabout 15% of the coating is freed from the device resulting in deliveryof ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the compliant balloon, at least about 75%of the coating is transferred from the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a compliant balloon coated with aformulation of about 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate˜1-2 months) and sirolimus with total loading of sirolimus˜20 μg.The device is placed at a coronary artery intervention site with theassistance of fluoroscopy to aid in positioning the device at the samelocation in each subject. Six animals are subjected to the procedureusing a coated balloon that does not have sirolimus in the coating.After deployment and removal of the device, 3 control animals aresacrificed at 1 hour post deployment and serum and tissue samples arecollected. The 3 remaining control animals are sacrificed at 56 dayspost deployment. During the course of the study, serum samples arecollected from control and drug-treated animals every five days. Thedrug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, 7days, 14 days, 28 days, 42 days and 56 days post deployment. The tissueand serum samples may be subjected to analysis for sirolimusconcentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is a cutting angioplasty catheter and the substrateis the balloon of the catheter) may be used to determine the percent ofcoating freed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β) and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe indicated by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

In-vitro testing: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon.

Method for the determination of sirolimus levels: Media may be assayedfor sirolimus content using HPLC. Calibration standards containing knownamounts of drug are to determine the amount of drug eluted. The multiplepeaks present for the sirolimus (also present in the calibrationstandards) are added to give the amount of drug eluted at that timeperiod (in absolute amount and as a cumulative amount eluted). HPLCanalysis is performed using Waters HPLC system, set up and run on eachsample as provided in the Table 1 below using an injection volume of 100μL.

TABLE 1 Time point % Ammonium Acetate Flow Rate (minutes) % Acetonitrile(0.5%), pH 7.4 (mL/min) 0.00 10 90 1.2 1.00 10 90 1.2 12.5 95 5 1.2 13.5100 0 1.2 14.0 100 0 3 16.0 100 0 3 17.0 10 90 2 20.0 10 90 0

In-vitro Mass Loss test: One sample of the coated compliant balloonprepared in Example 1 is weighed on a microbalance and then secured to aballoon catheter. A segment of optically clear TYGON® B-44-3 tubing withO.D.=0.125″, I.D.=0.0625″ (Available from McMaster-Carr Part Number:5114K11 (www.mcmaster.com)) is filled with phosphate-buffered salinesolution and immersed in a water bath at 37° C. to mimic physiologicalconditions of deployment into a subject. The coated balloon is insertedinto the tubing and the balloon is inflated to at least 25% below theballoon's nominal pressure to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. After drying, the balloon is removed from the guidewire, furtherdried and weighed on a microbalance. Comparison of the pre- andpost-deployment weights indicates how much coating is freed,dissociated, and/or transferred from the balloon. This analysis mayinstead and/or alternatively include testing of the tubing to determinethe amount of coating freed, dissociated, and/or transferred from thedevice during this in-vitro test.

In-vitro Coating test: One sample of the coated compliant balloonprepared in Example 1 is secured to a balloon catheter. A segment ofoptically clear TYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″(Available from McMaster-Carr Part Number: 5114K11 (www.mcmaster.com))is filled with phosphate-buffered saline solution and immersed in awater bath at 37° C. to mimic physiological conditions of deploymentinto a subject. The coated balloon is inserted into the tubing and theballoon is inflated to at least 25% below the balloon's nominal pressureto mechanically transfer the coating from the balloon to the tubingwall. The balloon is deflated and removed from the tubing. The sectionof tubing exposed to the deployed balloon is cut away from the remainderof the tubing and the interior of the excised tubing rinsed with a smallamount of ethanol and an amount of methylene chloride to make up 25 mLtotal volume of rinsings which are collected in a flask for analysis.Analysis by HPLC as described above is performed to determine the amountof material freed, dissociated, and/or transferred from the balloon.This analysis may instead and/or alternatively include testing of thesubstrate itself to determine the amount of coating freed, dissociated,and/or transferred from the device during this in-vitro test.

In-vitro testing: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of resectedcoronary artery from Yucatan miniature swine is positionally fixed andfilled with phosphate-buffered saline solution and immersed in a waterbath at 37° C. to mimic physiological conditions of deployment into asubject. The coated balloon is inserted into the artery and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the arterial wall.The balloon is deflated and removed from the artery. The section ofartery exposed to the deployed balloon is cut away from the remainder ofthe artery section, placed into a tissue homogonizer and the homogonizedmaterial is extracted with methylene chloride to make up 25 mL totalvolume of rinsings which are collected in a flask for analysis. Analysisby HPLC as described above is performed to determine the amount ofmaterial freed, dissociated, and/or transferred from the balloon. Thisanalysis may instead and/or alternatively include testing of thesubstrate itself to determine the amount of coating freed, dissociated,and/or transferred from the device during this in-vitro test.

For embodiments related to non-vascular or non-lumenal applications,e.g. a tumor site or other cavity or a cannulized site, the sametechnique is employed with the modification that the tissue to beassayed is resected from the tissue adjoining cavity receiving drugtreatment.

In-vitro testing: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of resectedcoronary artery from Yucatan miniature swine is positionally fixed andfilled with phosphate-buffered saline solution and immersed in a waterbath at 37° C. to mimic physiological conditions of deployment into asubject. The coated balloon is inserted into the artery and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the arterial wall.The balloon is deflated and removed from the artery. The section ofartery exposed to the deployed balloon is cut away from the remainder ofthe artery section and incised lengthwise to lay open the artery.Optical microscopy is performed on the interior of artery to determinethe presence and amount of coating transferred to the artery and/or theamount of coating transferred from the balloon. The tissue sample isalso subjected to TEM-SEM analysis.

In-vitro testing of release kinetics: One sample of the coated compliantballoon with total loading of sirolimus˜20 μg prepared in Example 1 issecured to a balloon catheter. A flask containing exactly 25 mL of pH7.4 aqueous phosphate buffer equilibrated to 37° C. equipped formagnetic stirring is prepared. Into this flask is placed the coatedballoon and the catheter portion of the apparatus is secured such thatthe balloon does not touch the sides of the flask. The balloon isinflated to 120 psi with sterile water. Aliquots of 100 μL are removedprior to addition of the balloon, after placement of the balloon butprior to inflation of the balloon, and at regular time intervals of 2,4, 6, 8, 10, 12, and 14 minutes. Upon removal of each aliquot anequivalent volume of aqueous buffer is added to maintain the volume at25 mL. The aliquots are analyzed by HPLC as described above for theconcentration of sirolimus.

In-vitro testing for distal flow particulates: One sample of the coatedcompliant balloon prepared in Example 1 is secured to a guidewireincorporating a porous filter of 100 micron pore size, such as theCordis AngioGuard emboli capture guidewire. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing, the proximal end of thetubing surrounding the guidewire sealed with epoxy, and a hypodermicneedle which is attached to an infusion pump and reservoir of 37° C.phosphate-buffered saline solution is inserted into the tubing proximalto the balloon assembly. The flow of saline is commenced, the distalfilter is deployed and the balloon is inflated to at least 25% below theballoon's nominal pressure to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. The filter is deployed for 5 minutes after removal of theballoon, the flow of saline is halted, the tubing cut adjacent to theepoxy seal, the filter retracted and removed from the tubing. Thecontent of the filter is analyzed.

In-vitro testing for distal flow particulates: One sample of the coatedcompliant balloon prepared in Example 1 is secured to a guidewire. Asegment of optically clear TYGON® B-44-3 tubing with O.D.=0.125″,I.D.=0.0625″ (Available from McMaster-Carr Part Number: 5114K11(www.mcmaster.com)) is filled with phosphate-buffered saline solutionand immersed in a water bath at 37° C. to mimic physiological conditionsof deployment into a subject and the distal end of the tubing isconnected to a turbidity light scattering detector as described inAnalytical Ultracentrifugation of Polymers and Nanoparticles, W. Machtleand L. Borger, (Springer) 2006, p. 41. The coated balloon is insertedinto the proximal end of the tubing, the proximal end of the tubingsurrounding the guidewire sealed with epoxy, and a hypodermic needlewhich is attached to an infusion pump and reservoir of 37° C.phosphate-buffered saline solution is inserted into the tubing proximalto the balloon assembly. The flow of saline is commenced, a baseline forlight transmission through the detector is established and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the tubing wall.The balloon is deflated and removed from the tubing. The flow ismaintained for 10 minutes after removal of the balloon, and the flow isanalyzed for the presence of particles based on detector response.

Drug-Delivery Balloon (2)—Non-Compliant Balloon

A non-compliant balloon is coated with a material comprising a polymerand an active agent. The coated non-compliant balloon is positioned atthe intervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of thenon-compliant balloon from the intervention site, at least about 5% toat least about 30% of the coating is freed from the surface of thenon-compliant balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The intervention site is a vascular lumen wall. Uponinflation of the non-compliant balloon, at least about 50% of thecoating is freed from the device at the intervention site.

In another example, a non-compliant balloon is coated with a formulationof PLGA+sirolimus with total loading of sirolimus˜20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the non-compliant balloon, about 5%to about 15% of the coating is freed from the device resulting indelivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate˜1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate˜28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 1 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the non-compliantballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Example 3 In Vivo Delivery of Rapamycin from Coated Balloons SirolimusCoated Balloon Formulation Tested in Rabbits

GHOST Rapid Exchange (Rx) Catheter was used in this example. Ghost3.0×18 mm Rx catheter balloons were coated and used in animal study. Thestudy was conducted according to the following design. Several testswere run to determine in-vivo drug delivery characteristics of therapamycin from the coated balloons.

The first test included expansion of the coated balloons in rabbit iliacarteries. 8 coated balloons were manufactured and tested in 4 rabbits.Four of the coated balloons were inflated in pre-dilated arteries (rightiliac) for 60 seconds, and four of the coated balloons were inflated innon-dilated arteries (left iliac) for 60 seconds. The amount of drug(sirolimus) found in the arterial tissue at the site of expansion wasdetermined. The following table indicates the results of the testing ofthese arteries for sirolimus concentration in arterial tissue and totalamount of sirolimus in each artery. Drug coated balloons in right iliacarteries were inflated/deflated about 10-20 min before sacrifice. Drugcoated balloons in left iliac arteries were inflated/deflated about 5-15min before sacrifice.

Average Total Sirolimus Sirolimus per Artery Iliac Artery (ng/mg) SDAverage (μg) SD Right Iliac (denuded) (n = 4) 178.3 32.1 5.4 1.1 LeftIliac (uninjured) (n = 4) 216.1 122.4 3.9 1.7 Combined Right + LeftIliac 197.2 85.3 4.7 1.6 Arteries (n = 8)

The following table indicates the raw data of the testing of these samearteries for the total amount of sirolimus in each artery. It alsoindicates a calculated transfer efficiency of sirolimus to the rabbitiliac arteries and the estimated time that the artery was exposed toblood flow. The percent (%) sirolimus transferred to the artery wascalculated using an estimated total amount of sirolimus on the balloon.The estimated total amount of sirolimus on the balloon which was basedon the batch average total amount of sirolimus coated on the same batchof balloons as the test sample balloon as determined by UV-Viscometrictesting of the balloon. The estimated time that the artery was exposedto blood flow was the amount of time between balloon inflation and theballoon testing, and/or the time between balloon inflation and until theanimal was sacrificed and the artery extracted for testing by HPLC forcontent of drug.

Estimated Time Artery Total Exposed Sirolimus to per % Sirolimus BloodArtery Transferred Flow Rabbit # Balloon # (μg) to Artery (min) #1 RightIliac Artery N185 5.0 7.76% 20 #1 Left Iliac Artery N157 3.2 5.58% 15 #2Right Iliac Artery N164 7.0 12.62%  10 #2 Left Iliac Artery N167 5.08.98% 5 #3 Right Iliac Artery N175 5.1 9.17% 10 #3 Left Iliac ArteryN178 1.8 2.88% 5 #4 Right Iliac Artery N191 4.5 7.59% 15 #4 Left IliacArtery N117 5.7 7.95% 10 Tracking Average — 4.7  7.8% — SD — 1.6  2.8% —

The following table indicates the blood concentrations of sirolimus(whole blood) taken from the animals used in this test. A baselineconcentration of sirolimus was taken prior to exposure to the coatedballoon for each animal, that is, taken before balloon inflation. Thewhole blood samples were taken 5 to 15 minutes after the second balloonwas inflated in each animal, since two coated balloons were delivered toeach animal in this test. The results indicated in the table below,therefore, indicate the cumulative whole blood Sirolimus concentrationfrom the inflation of 2 drug coated balloons per animal. The totalsirolimus in blood is based on 56 mL of blood per kg (i.e. per kg weightof the rabbit tested).

Extraction Conc. Est. Total Sirolimus Rabbit # (ng/mL) in Blood (μg) #1Baseline Below Quality Level — #2 Baseline Below Quality Level — #3Baseline Below Quality Level — #4 Baseline Below Quality Level — #1 (15min) 11.4 2.7 #2 (5 min) 30.8 8.2 #3 (5 min) 22.2 5.9 #4 (10 min) 19.34.8 Average (5-15 min) 20.9 5.4 SD 8.0 2.3

The following table indicates the concentrations of sirolimus on eachballoon used in this test following the test itself, to indicate thepercent (%) of sirolimus lost following the test procedure. As notedabove, each of the balloons was tracked to the respective artery, andinflated for 60 seconds (1 minute), then deflated and removed from theanimal and tested for the percent of sirolimus remaining on the balloon.The percent (%) sirolimus lost is based on the amount of sirolimusremaining on the balloon following the test and the total amount ofsirolimus coated on the balloon which is estimated from the balloonbatch average as tested using UV-Viscometric methods. The variableswhich contribute to the amount (or percent) of sirolimus lost includethe following: Balloon insertion into iliac (via jugular+aorta); Bloodflow; Pleat/Fold/Sheath methods and procedures; ˜10% lost duringshipping; and/or Balloon inflation/contact with artery wall.

Total Sirolimus per % Sirolimus Balloon ID Balloon (μg) Lost Rabbit #1RIA Balloon N185 13.2 79.3% Robbie #1 LIA Balloon N157 17.3 69.9% Rabbit#2 RIA Balloon N164 4.8 91.5% Rabbit #2 LIA Balloon N167 11.7 79.1%Rabbit #3 RIA Balloon N175 16.0 71.4% Rabbit #3 LIA Balloon N178 14.777.0% Rabbit #4 RIA Balloon N191 9.6 83.6% Rabbit #4 LIA Balloon N11714.9 79.1% Tracking Average 12.8 78.9% SD 4.0 6.8%

In another test, tracking studies were conducted. The test comprisestracking 4 coated balloons to the aorta of a rabbit. Each of 4 coatedballoons was inserted, tracked to the aorta of the rabbit, and left inthe aorta for 2 minutes without inflating the balloon. Followinginsertion, tracking, and resting the balloon in the aorta for 2 minutes,the catheter including the coated balloon was removed from the animal.

The following table indicates the concentrations of sirolimus on eachballoon used in this test following the test itself, to indicate thepercent (%) of sirolimus lost following the test procedure. The percent(%) sirolimus lost is based on the amount of sirolimus remaining on theballoon following the test and the total amount of sirolimus coated onthe balloon which is estimated from the balloon batch average as testedusing UV-Viscometric methods. The variables which contribute to theamount (or percent) of sirolimus lost include the following: Ballooninsertion into iliac (via jugular+aorta); Blood flow; Pleat/Fold/Sheathmethods and procedures; and/or ˜10% lost during shipping.

Total Sirolimus per % Sirolimus Balloon ID Balloon (μg) Lost Tracking #1Balloon (N120) 23.6 66.9% Tracking #2 Balloon (N160) 20.8 63.9% Tracking#3 Balloon (N166) 19.0 66.0% Tracking #4 Balloon (N176) 22.0 65.5%Tracking Average 21.3 65.6% SD 2.0 1.3%

Sirolimus quantification was performed on the balloons and blood samplesfrom the previous two tests (as indicated in the “Total Sirolimus perBalloon (ug)” columns of the previous two tables, and as indicated inthe blood concentration table generally). That is, sirolimus content wasdetermined from the 8 balloons inflated in rabbit iliac arteries, the 4balloons tracked to but not inflated in rabbit aorta, and the 8 wholeblood samples (2 samples/rabbit). The liver, kidney, spleens, hearts andlungs were stored (80° C.) for later drug analysis.

In summary, the tests performed in this Example indicate the following:197.2±85.3 ng/mg of Sirolimus embedded in artery walls. The Efficiencyof Sirolimus transferred from balloons to artery walls was 7.8±2.8%. Theamount of sirolimus washed away into circulation was 5.4±2.3 μg.Following inflation in arteries, 78.9±6.8% of the sirolimus coated onthe balloon was removed from the balloon. Prior to inflation in thearteries, 65.6±1.3% of the sirolimus coated on the balloon was removedfrom the balloon. For reference, 50-100 μg of sirolimus was coated oneach balloon. From 1% to 5% of the drug (sirolimus) was transferred tothe artery. 1 ng of sirolimus per mg tissue was found during the testingas described in this example.

Example 4 In Vivo Delivery of Rapamycin from Coated Balloons

Binding agents may be incorporated into the coating to improve activeagent retention in the artery. Example binding agents include cationicagents and/or positively charged molecules. An example binding agent maybe a surfactant. Other agents may also and/or alternatively be used.Binding agents may include, for non-limiting example, at least one of:Polyarginine, Polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethylcellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI(Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB(Dimethylditetradecylammonium bromide). In some embodiments of thedevices, coatings and/or methods provided herein the coating comprises apositive surface charge on a surface of the coating configured tocontact the treatment site.

In some embodiments the surfactant comprises at least one of a primaryamine having pH<10, and a secondary amine having pH<4. In someembodiments surfactant comprises octenidine dihydrochloride. In someembodiments the surfactant comprises a permanently charged quaternaryammonium cation. In some embodiments the permanently charged quaternaryammonium cation comprises at least one of: an Alkyltrimethylammoniumsalt such as cetyl trimethylammonium bromide (CTAB), hexadecyl trimethylammonium bromide, cetyl trimethylammonium chloride (CTAC);Cetylpyridinium chloride (CPC); Polyethoxylated tallow amine (POEA);Benzalkonium chloride (BAC); Benzethonium chloride (BZT);5-Bromo-5-nitro-1,3-dioxane; Dimethyldioctadecylammonium chloride; andDioctadecyldimethylammonium bromide (DODAB). In some embodiments thesurfactant comprises at least one of: didodecyldimethylammonium bromide(DMAB), linear isoform Polyethylenimine (linear PEI), Branched Low MWPolyethylenimine (PEI) (of about <25 KDa), Branched Low MWPolyethylenimine (PEI) (of about <15 KDa), Branched Low MWPolyethylenimine (PEI) (of about <10 KDa), Branched High MWPolyethylenimine (of about >/=25 KDa), Poly-L-Arginine (average ornominal MW of about 70,000 Da), Poly-L-Arginine (average or nominalMW>about 50,000 Da), Poly-L-Arginine (average or nominal MW of about5,000 to about 15,000 Da), Poly-L-Lysine (average or nominal MW of about28,200 Da), Poly-L-Lysine (average or nominal MW of about 67,000 Da),Poly Histidine, Ethylhexadecyldimethylammonium Bromide, DodecyltrimethylAmmonium Bromide, Tetradodecylammonium bromide, DimethylditetradecylAmmonium bromide, Tetrabutylammonium iodide, DEAE-Dextran hydrochloride,and Hexadimethrine Bromide. In some embodiments, the molecular weight ofthe binding agent is controlled. In some embodiments, the average sizeof the binding agent is controlled.

In some embodiments of the devices, coatings and/or methods providedherein the binding agent and the active agent are mixed and depositedtogether on the device. In some embodiments, the active agent andbinding agent are lyophilized prior to deposition on the device. In someembodiments dry particles of the active agent and binding agent aregenerated in another manner familiar to one of skill in the art and thencoated on the balloon or other medical device as described herein, suchas by an eSTAT coating process. In some embodiments of the devices,coatings and/or methods provided herein the surfactant is deposited on aballoon after the active agent is deposited thereon.

The positive surface charge of the coating may be about 20 mV to about40 mV. The positive surface charge may be at least one of: at leastabout 1 mV, over about 1 mV, at least about 5 mV, at least about 10 mV,about 10 mV to about 50 mV, about 20 mV to about 50 mV, about 10 mV toabout 40 mV, about 30 mV to about 40 mV, about 20 mV to about 30 mV, andabout 25 mV to about 35 mV.

In some embodiments the average molecular weight of the binding agent iscontrolled. For example, Polyarginine may have an average molecularweight of 70 kDa, 5-15 kDa, another controlled molecular weight, or acombination thereof. In some embodiments the molecular weight of thebinding agent is controlled. For example, in some embodiments,Polyarginine is the binding agent and at least 75% of the Polyarginineas is 70 kDa, 5-15 kDa, or another controlled molecular weight. In someembodiments, Polyarginine is the binding agent and at least 50% of thePolyarginine as is 70 kDa, 5-15 kDa, or another controlled molecularweight. In some embodiments, Polyarginine is the binding agent and atleast 90% of the Polyarginine as is 70 kDa, 5-15 kDa, or anothercontrolled molecular weight. In some embodiments, Polyarginine is thebinding agent and at least 95% of the Polyarginine as is 70 kDa, 5-15kDa, or another controlled molecular weight. In some embodiments,Polyarginine is the binding agent and at least 98% of the Polyarginineas is 70 kDa, 5-15 kDa, or another controlled molecular weight. In someembodiments, Polyarginine is the binding agent and at least 99% of thePolyarginine as is 70 kDa, 5-15 kDa, or another controlled molecularweight.

In some embodiments, the size of the active agent in the coating iscontrolled in order to improve drug retention in the artery. Fornon-limiting example, in the case of sirolimus as an active agent, thesirolimus may have an average size (mean diameter) of at least one of:1.5 μm, 2.5 μm, 645 nm, 100-200 nm, another controlled size, or acombination thereof. In some embodiments, the active agent is sirolimusand wherein the sirolimus has a median size of at least one of: 1.5 μm,2.5 μm, 645 nm, 100-200 nm, another controlled size, or a combinationthereof. In some embodiments, the active agent is sirolimus and whereinthe sirolimus has an average size (mean diameter) of at least one of:about 1.5 μm, about 2.5 μm, about 645 nm, about 100-200 nm, anothercontrolled size, or a combination thereof. In some embodiments, theactive agent is sirolimus and wherein the sirolimus has a median size ofat least one of: about 1.5 μm, about 2.5 μm, about 645 nm, about 100-200nm, another controlled size, or a combination thereof. In someembodiments the size of the active agent is controlled. For example, insome embodiments, sirolimus is the active agent and at least 75% of thesirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm, or anothercontrolled size. In some embodiments, sirolimus is the active agent andat least 50% of the sirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm,or another controlled size. In some embodiments, sirolimus is the activeagent and at least 90% of the sirolimus as is 1.5 μm, 2.5 μm, 645 nm,100-200 nm, or another controlled size. In some embodiments, sirolimusis the active agent and at least 95% of the sirolimus as is 1.5 μm, 2.5μm, 645 nm, 100-200 nm, or another controlled size. In some embodiments,sirolimus is the active agent and at least 98% of the sirolimus as is1.5 μm, 2.5 μm, 645 nm, 100-200 nm, or another controlled size. In someembodiments, sirolimus is the active agent and at least 99% of thesirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm, or anothercontrolled size. The active agent may be, on average, at least one of:at most 5 microns, over 1 micrometer, between 1 micrometer and 5micrometers, about 1.5 micrometers on average, and about 2.5 micrometerson average.

In some embodiments, the ratio of the active agent to the binding agentis controlled. In some embodiments, the ratio of active agent to bindingagent is 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:20, 2:1, 3:1, 4:1, 5:1, 10:1,15:1, 20:1, 3:2, 2:3, 5:2, 5:3, 2:5, 3:5, or another controlled ratio.

In some embodiments, the coating may comprise nanoparticles, and thenanoparticles may comprise an active agent and a polymer.

Multiple coating formulations were coated on balloons 3.0×18 or 3.0×17balloons of GHOST Rapid Exchange (Rx) Catheters and delivered in rabbitsto their iliac arteries. The arterial tissue of the rabbits wasextracted at certain time points up to 72 hours and the amount of drugfound in the arterial tissue was determined by methods known to one ofskill in the art, such as by HPLC methods testing the arterial tissue orby UV-Viscometric methods looking at loss of coating or agent during theprocedure, expressed in ng drug (Sirolimus) per mg of tissue, indicatedin the following table (sample size indicated therein). In most cases,the necropsy time points were 5 minutes+/−5%, 24 h+/−5%, and 72hrs+/−5%. For example, the necropsy was conducted about 5 minutes, 24 h,or 72 hr after deflation of the second drug coated balloon per animal(+/−5% of the time point) where two vessels were used in the study.

5 minutes 24 hours 72 hours Formulation Sirolimus Sirolimus SirolimusComposition Concentration (ng/mg) Concentration (ng/mg) Concentration(ng/mg) F1 127.9 ± 80.2 (n = 20)  0.8 ± 0.9 (n = 12) N/A F2 N/A  10.4 ±14.7 (n = 2) N/A F3  39.0 ± 11.6 (n = 8)  25.2 ± 20.2 (n = 10)  4.7 ±3.7 (n = 7) F4  90.6 ± 59.1 (n = 4)  1.3 ± 1.9 (n = 2) N/A F5  6.6 ± 2.1(n = 4)  15.2 ± 27.6 (n = 6) BQL (n = 4) F6 226.0 ± 22.6 (n = 2)  5.4 ±7.6 (n = 2) N/A F7  97.2 ± 54.7 (n = 4)  40.5 ± 25.0 (n = 6)  2.7 ±1.7(n = 4) F8 N/A BQL (n = 2) N/A F9 N/A BQL (n = 2) N/A F10 100.5 ±17.6 (n = 4)  28.4 ± 10.9 (n = 6) 10.2 ± 5.6 (n = 4) F11  92.4 ± 18.9 (n= 4)  6.4 ± 11.7 (n = 6)  3.9 ± 5.7 (n = 4) F12 N/A BQL (n = 2) N/A F13AN/A BQL (n = 2) N/A F13B  74.2 ± 13.1 (n = 4)  14.0 ± 11.7 (n = 6)*  0.9± 1.7 (n = 4) F13C N/A BQL (n = 2) N/A F13D N/A  53.0 ± 5.5 (n = 2) N/AF14A N/A BQL (n = 2) N/A F14B N/A BQL (n = 2) N/A F14C Unable to makeformulation F14D N/A BQL (n = 2) N/A F15 114.7 ± 66.2 (n = 4) 108.2 ±119.8 (n = 4) 46.5 ± 46.1 (n = 4) F16  73.7 ± 38.5 (n = 4) N/A BQL (n =4) F17 404.5 ± 96.0 (n = 4) N/A  0.9 ± 1.1 (n = 4) F18 191.3 ± 40.0 (n =4) N/A  1.4 ± 2.8 (n = 4) *Two studies, were conducted and data wascombined here, Study 1: n = 2 8.1 +/− 5.2, Study 2: n = 4 17.0 +/− 13.5.

The results were calculated as total amount of sirolimus extracted inthe artery, as indicated in the following table:

Formulation 5 minutes 24 hours 72 hours Composition Sirolimus amount(μg) Sirolimus amount (μg) Sirolimus amount (μg) F1 4.7 ± 1.6 (n = 8) —— F1 (2^(nd) lot) 5.9 ± 1.6 (n = 12)  0.1 ± 0.1 (n = 12) — F2 —  0.4 ±0.6 (n = 2) — F3 study 1** 2.6 +/− 0.9 (n = 4  0.8 +/− 0.4 (n = 4)  0.3+/− 0.2 (n = 4) F3 study 2** 2.4 +/− 2.3 (n = 4)  0.8 +/− 1.0 (n = 4) 0.4 +/− 0.5 (n = 3*) F3 (1^(st) lot**) 3.0 ± 1.5 (n = 6)  0.8 ± 0.5 (n= 8)  0.2 ± 0.1 (n = 6) F3 (2^(nd) lot**) 1.0 ± 0.4 (n = 2)  1.2 ± 1.6(n = 2) 1.0 (n = 1) F4 4.5 ± 3.2 (n = 4) 0.07 ± 0.1 (n = 2) — F5 0.4 ±0.2 (n = 4)  0.6 ± 1.0 (n = 6) BQL (n = 4) F6 8.8 ± 1.2 (n = 2)  0.2 ±0.2 (n = 2) — F7 6.2 ± 3.7 (n = 4)  2.1 ± 1.3 (n = 6)  0.2 ± 0.1 (n = 4)F8 — BQL (n = 2) — F9 — BQL (n = 2) — F10 2.0 ± 0.4 (n = 4)  1.0 ± 0.8(n = 6)  0.2 ± 0.1 (n = 4) F11 2.3 ± 0.5 (n = 4)  0.3 ± 0.5 (n = 6)  0.1± 0.1 (n = 4) F12 — BQL (n = 2) — F13A — BQL (n = 2) — F13B 2.2 ± 0.4 (n= 4)  0.4 ± 0.3 (n = 6) 0.02 ± 0.03 (n = 4) F13C — BQL (n = 2) — F13D — 0.8 ± 0.2 (n = 2) — F14A — BQL (n = 2) — F14B — BQL (n = 2) — F14D —BQL (n = 2) — F15 4.8 ± 0.6 (n = 4)  2.0 ± 1.9 (n = 4)  1.2 ± 1.0 (n =4) F16 2.2 ± 0.8 (n = 4) — BQL (n = 4) F17 9.4 ± 2.7 (n = 4) — 0.02 ±0.03 (n = 4) F18 4.4 ± 0.9 (n = 4) — 0.03 ± 0.07 (n = 4) *one outlierremoved **note that data from F3 was divided two ways for analysis, bystudy and also by manufacturing lot, thus the same results arerepresented in both groups (study 1, 2 and lot 1, 2).

Certain formulations were selected for additional analysis, and theirtest results were normalized for the balloon length and the arterysegment size extracted. The following results were found for theseselected formulations:

Formulation 5 minutes - Sirolimus 24 hours - Sirolimus 72 hours -Sirolimus Composition Concentration (ng/mg) Concentration (ng/mg)Concentration (ng/mg) F1 278.5 ± 112.2 (n = 20)  2.3 ± 2.6 (n = 12) N/AF3  97.1 ± 49.3 (n = 8)  60.1 ± 39.4 (n = 10) 11.9 ± 10.7 (n = 7) F5 19.7 ± 6.4 (n = 4)  45.5 ± 82.9 (n = 6) BQL (n = 4) F7 291.5 ± 164.0 (n= 4) 121.5 ± 75.0 (n = 6)  8.0 ± 5.1 (n = 4) F10 167.5 ± 29.4 (n = 4) 58.8 ± 33.3 (n = 6) 17.1 ± 9.3 (n = 4) F11 153.9 ± 31.4 (n = 4)  17.1 ±34.8 (n = 6)  6.5 ± 9.5 (n = 4) F13B 130.9 ± 23.2 (n = 4)  24.7 ± 20.6(n = 6)  1.5 ± 3.0 (n = 4) F15 202.5 ± 116.8 (n = 4) 190.9 ± 211.5 (n =4) 82.0 ± 81.3 (n = 4) F16 130.0 ± 67.9 (n = 4) N/A BQL (n = 4) F17713.8 ± 169.5 (n = 4) N/A  1.6 ± 1.9 (n = 4) F18 337.5 ± 70.6 (n = 4)N/A  2.5 ± 5.0 (n = 4)

Certain formulations were selected for another analysis, andconcentration results were normalized for the artery weight (normalizedto 0.025 g). The following results were found for these selectedformulations.

5 minutes - Sirolimus 24 hours - Sirolimus 72 hours - SirolimusFormulation Composition Conc. (ng/mg) Conc. (ng/mg) Conc. (ng/mg) F1(LOT 1) (PLGA, Sirolimus 2.5 μm) 186.5 ± 62.7 (n = 8) N/A N/A F1 (LOT 2)(PLGA, Sirolimus 2.5 μm) 234.8 ± 66.0 (n = 12)  2.4 ± 2.3 (n = 12) N/AF3 (PLGA, Sirolimus 2.5 μm,  99.0 ± 61.6 (n = 8) 36.0 ± 27.3 (n = 10)12.8 ± 13.5 (n = 7) Polyarginine 70 kDa) F5 (PLGA, Sirolimus 2.5 μm,DMAB)  16.3 ± 6.3 (n = 4) 23.5 ± 39.9 (n = 6) BQL (n = 4) F7 (PLGA,Sirolimus 2.5 μm, PEI) 248.6 ± 147.7 (n = 4) 83.2 ± 53.6 (n = 6)  7.6 ±4.4 (n = 4) F10 (PLGA, Sirolimus 2.5 μm,  80.3 ± 14.9 (n = 4) 38.9 ±31.8 (n = 6)  9.2 ± 3.8 (n = 4) Polyarginine 70 kDa, PEI) F11 (PLGA,Sirolimus 2.5 μm, DEAE-  91.5 ± 19.5 (n = 4) 10.2 ± 21.3 (n = 6)  3.3 ±4.9 (n = 4) Dextran, TAB) F13B (PLGA, Sirolimus 645 nm,  87.6 ± 15.4 (n= 4) 17.4 ± 13.6 (n = 6)  0.6 ± 1.2 (n = 4) Polyarginine 70 kDa) F15(LOT 1) (PLGA, Sirolimus 1.5 μm, 192.6 ± 23.6 (n = 4) 78.2 ± 76.8 (n =4) 49.8 ± 41.8 (n = 4) Polyarginine 5-15 kDa)

In the rabbit arterial and blood tests noted in this example, thefollowing coating details and formulations were used.

-   -   F1 (Formulation 1) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and Sirolimus having an average size of 2.5        μm.    -   F2 (Formulation 2) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1 ratio of Sirolimus having an        average size of 2.5 μm to Polyarginine 70 kDa.    -   F3 (Formulation 3) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 1.5 μm or 2.5 μm to Polyarginine 70 kDa.    -   F4 (Formulation 4) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μm to DEAE-Dextran (Diethylaminoethyl        cellulose-Dextran).    -   F5 (Formulation 5) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1 ratio of Sirolimus having an        average size of 2.5 μm and DMAB (Didodecyldimethylammonium        bromide).    -   F6 (Formulation 6) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μm and DMAB (Didodecyldimethylammonium        bromide).    -   F7 (Formulation 7) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μm and PEI (Polyethyleneimine)    -   F8 (Formulation 8) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μm and TAB (Tetradodecylammonium bromide).    -   F9 (Formulation 9) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μm and DMTAB (Dimethylditetradecylammonium        bromide).    -   F10 (Formulation 10) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1:1 ratio of Sirolimus having an        average size of 2.5 μm to Polyarginine 70 kDa to PEI        (Polyethyleneimine)    -   F11 (Formulation 11) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1:1 ratio of Sirolimus having an        average size of 2.5 μm to TAB (Tetradodecykammonium bromide to        DEAE-Dextran (Diethylaminoethyl cellulose-Dextran).    -   F12 (Formulation 12) comprised PLGA Nanospheres (130 nm) where        the PLGA is 50:50 Lactic acid:Glycolic acid, and 6.3% Sirolimus.    -   F13A (Formulation 13A) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and Sirolimus having an average size of 645        nm    -   F13B (Formulation 13B) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to Polyarginine 70 kDa.    -   F13C (Formulation 13C) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1 ratio of Sirolimus having an        average size of 645 nm to DMAB (Didodecyldimethylammonium        bromide).    -   F13D (Formulation 13D) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to PEI (Polyethyleneimine)    -   F14A (Formulation 14A) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and Sirolimus having an average size of        100-200 nm.    -   F14B (Formulation 14B) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 100-200 nm to Polyarginine 70 kDa.    -   F14C (Formulation 14C) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1 ratio of Sirolimus having an        average size of 100-200 nm to DMAB (Didodecyldimethylammonium        bromide). Note that this formulation was not able to be made,        therefore, no animal study results were obtained.    -   F14D (Formulation 14D) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 100-200 nm to PEI (Polyethyleneimine)    -   F15 (Formulation 15) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 1.5 μm to Polyarginine 5-15 kDa.    -   F16 (Formulation 16) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 1.5 μm to Polyarginine 9-L-pArg.    -   F17 (Formulation 17) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to Polyarginine 5-15 kDa.    -   F18 (Formulation 18) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to Polyarginine 9-L-pArg.

With the exception of F12, all methods comprised using an RESS processfor coating the PLGA on the balloon, and using an eSTAT process forcoating the Sirolimus and the positive charged molecule to the balloon.The general process for coating was 1) Polymer coat by RESS processes,2) Sirolimus and binding agent coat (or sirolimus alone, if there was nobinding agent used in the formulation e.g. 14A) by eSTAT processes, 3)sinter the coated balloon. The binding agent (i.e. charged particle,surfactant, and/or cationic particle) was part of the Sirolimus coatingstep wherein the balloon was coated with both the Sirolimus and thebinding agent using an eSTAT process. Formulation 12 was coated on theballoon using only an eSTAT or an RESS process and a sinter step.

The sirolimus was mixed with the binding agent (e.g. the surfactant, thecationic particle, the charged molecule, for non-limiting example) ifpresent in the particular formulation in the following manner. Theprocess may be adapted to different binding agents and different activeagents, however, it is described herein as used with respect tosirolimus and the binding agents which were surfactants in theformulations noted in this example. Lyophilisation or “freeze drying”processed produced a dry powder of associated drug and binding agent(e.g. surfactant) suitable for depositing onto balloons via the eSTATmethod. Other processes familiar to one of skill in the art may be usedas an alternative to lyophilisation in order to associate the drug andbinding agent in a form suitable for deposition on the balloons via amethod described herein. In this example, rapamycin (sirolimus) wassuspended in water with a binding agent to coat the sirolimus withbinding agent. The well-suspended sirolimus and binding agent solutionwas frozen, retaining the sirolimus and binding agent assembly, and thewater was removed by sublimation to produce the dry sirolimus andbinding agent material.

A pre-lyophilisation set of steps may be used in the process of creatingthe dried sirolimus and binding agent solution for use in the eSTATcoating process. The solution created thereby may be used in a freezedryer. The desired quantity of drug (e.g. sirolimus) and binding agentwere weighed out into a 100 mL Schott bottle. Then 50 mL of water isadded, in increments of 10 mL, to the Schott bottle. During eachincrement the solution is mixed with a stir rod to insure the sirolimusis being wetted. After the 50 mL is added the solution is sonicated in abath sonicator (Branson 1510) for 1 hr. In the final pre-lyophilisationstep, the well-suspended solution is carefully transferred to a 50 mLconical centrifuge tube using a plastic pipette; unsuspended sirolimusand/or binding agent particles (typically found floating on the surfaceof the suspension, are not transferred. Note: the efficiency of thesirolimus suspension by the binding agent affects the actual sirolimusto surfactant ratio of the transferred solution and the final recoveredpowder, often changing it from the initial sirolimus and binding agentratio weighed out.

The Lyophilisation steps may be as follows: The recovered suspension inthe 50 mL centrifuge tube is immersed in liquid nitrogen until thesolution is completely frozen. Parafilm is used to cover the opening ofthe tube containing the frozen suspension, while perforations are madein the film to allow escape of the vapor phase water. The tubecontaining the frozen sample is loaded into a freeze dryer containmentvessel and the vessel is attached to one of the freeze dryer stations.The switch above the nozzle for the loaded station is activated to beginthe process. The lyophilisation step is complete when all of the frozenmoisture is visibly absent from the tube. The sample, which may exist asa xerogel following lyophilisation, is easily converted to afree-flowing dry powder by shaking or stirring when the process iscomplete. It usually takes 1-2 days for a sample prepared as describedabove to complete the lyophilisation step. Note: the freeze-drier mayneed to be periodically be defrosted to remove the accumulated moisturefrom the samples in order to work effectively.

The following steps were taken to make the sirolimus and binding agentdry solution in the eSTAT coating process of the balloons (which hadbeen pre-coated using an RESS process with PLGA as noted elsewhereherein). Measure out required quantities of sirolimus and binding agentinto a 100 mL Schott bottle. Add 50 mL of water, in increments of 10 mL,to the Schott bottle. During each increment use a stir rod to mix thesirolimus and binding agent solution. After 50 mL of water is added,sonicate the solution for 1 hr. After sonication use a plastic pipetteto transfer the suspended solution to a 50 mL centrifuge tube. Avoidtransfer of any unsuspended sirolimus and binding agent particles. Place50 mL conical tube (without lid) in liquid nitrogen until solution iscompletely frozen. Cover the top of the conical tube with parafilm andmake holes in film for water to travel through. Seal the 50 mL conicalbottle in the lyophilisation vessel and connect the vessel to a freezedryer nozzle station. Turn switch above the nozzle to evacuate the airfrom the vessel. Keep sample on the freeze-drier until all water hasbeen removed (typically 1-2 days)

Rabbit Blood Concentration results follow. The amount of drug as aconcentration per mL of blood was determined for several formulations,as indicated in the following table. BQL herein means below quantitationlimit (1-2 ng/ml with respect to whole blood quantitation of sirolimus)

Formula- Sirolimus in whole blood (ng/mL) tion 5 min 24 hours 72 hoursF1 20.9 ± 8.0 (n = 4) N/A N/A F1  5.7 ± 1.6 (n = 6) BQL (n = 6) N/A(2^(nd) lot) F2 N/A BQL (n = 1) N/A F3  8.9 ± 4.4 (n = 2) BQL (n = 2)BQL (n = 2) (Study 1)* F3  7.1 ± 2.2 (n = 2) BQL (n = 2) BQL (n = 2)(Study 2)* F3  7.7 ± 3.7 (n = 3)  0.8 ± 0.7 (n = 3) BQL (n = 3) (1^(st)lot)* F3  5.5 (n = 1) BQL (n = 1) BQL (n = 1) (2^(nd) lot)* F4 N/A BQL(n = 1) N/A F5 0.99 ± 0.1 (n = 2) BQL (n = 3) BQL (n = 2) F6 N/A 2.72 (n= 1) N/A F7 11.2 ± 3.4 (n = 2)  1.7 ± 0.3 (n = 3) 1.3 ± 0.9 (n = 2) F8N/A BQL (n = 1) N/A F9 N/A 2.06 (n = 1) N/A F10 BQL (n = 2) 0.36 ± 0.6(n = 3) BQL (n = 2) F11 10.1 ± 0.2 (n = 2) BQL (n = 3) BQL (n = 2) F12N/A BQL (n = 1) N/A F13A N/A 1.13 (n = 1) N/A F13B  6.4 ± 3.1 (n = 2) 1.0 ± 0.9 (n = 3)** BQL (n = 2) F13C N/A BQL (n = 1) N/A F13D N/A 2.99(n = 1) N/A F14A N/A BQL (n = 1) N/A F14B N/A BQL (n = 1) N/A F14D N/ABQL (n = 1) N/A F15  5.7 ± 3.2 (n = 2)  1.8 ± 0.01 (n = 2) BQL (n = 2)F16 76.8 ± 89.4 (n = 2) N/A BQL (n = 2) F17 25.6 ± 1.3 (n = 2) N/A BQL(n = 2) F18 23.5 ± 3.3 (n = 2) N/A 0.5 ± 0.8 (n = 2) *note that datafrom F3 was divided two ways for analysis, by study and also bymanufacturing lot, thus the same results are represented in both groups(study 1, 2 versus lot 1, 2). **This data represents two lots of coatedballoons, for one of the lots the sirolimus in whole blood (ng/mL)results were: (n = 2), 0.7 +/− 1.0The amount of drug as a total amount found in the arterial tissue wasdetermined for several formulations, as indicated in the followingtable.

Sirolimus in whole blood (μg) Formula- based on 56 mL blood per kg tion5 min 24 hours 72 hours F1  5.4 ± 2.3 (n = 4) N/A N/A F1  1.0 ± 0.3 (n =6) BQL (n = 6) N/A (2^(nd) lot) F2 N/A BQL (n = 1) N/A F3  1.5 ± 0.7 (n= 3) BQL (n = 2) BQL (n = 2) (Study 1)* F3  1.6 ± 0.5 (n = 1) BQL (n =2) BQL (n = 2) (Study 2)* F3  1.7 ± 0.6 (n = 3) 0.1 ± 0.1 (n = 3) BQL (n= 3) (1^(st) lot)* F3  1.2 (n = 1) BQL (n = 1) BQL (n = 1) (2^(nd) lot)*F4 N/A BQL (n = 1) N/A F5 0.18 ± 0.2 (n = 2) BQL (n = 3) BQL (n = 2) F6— 0.4 (n = 1) N/A F7  1.9 ± 0.6 (n = 2) 0.3 ± 0.1 (n = 3) 0.25 ± 0.01 (n= 2) F8 N/A BQL (n = 1) N/A F9 N/A 0.3 (n = 1) N/A F10 BQL (n = 2) 0.1 ±0.1 (n = 3) BQL (n = 2) F11  2.0 ± 0.05 (n = 2) BQL (n = 3) BQL (n = 2)F12 N/A BQL (n = 1) N/A F13A N/A 0.2 (n = 1) N/A F13B  1.3 ± 0.7 (n = 2)0.2 ± 0.2 (n = 3) BQL (n = 2) F13C N/A BQL (n = 1) N/A F13D N/A 0.6 (n= 1) N/A F14A N/A BQL (n = 1) N/A F14B N/A BQL (n = 1) N/A F14D N/A BQL(n = 1) N/A F15  1.2 ± 0.7 (n = 2) 0.4 ± 0.0 (n = 2) BQL (n = 2) F1618.7 ± 21.9 (n = 2) N/A BQL (n = 2) F17  6.2 ± 0.3 (n = 2) N/A BQL (n =2) F18  5.5 ± 0.6 (n = 2) N/A 0.12 ± 0.17 (n = 2) *note that data fromF3 was divided two ways for analysis, by study and also by manufacturinglot, thus the same results are represented in both groups (study 1, 2versus lot 1, 2).

The various formulations had the following average amount of sirolimuscoated on each of the balloons tested in the rabbit arteries. These wereaverage amounts of drug found on sample balloons coated according to thesame procedures noted herein and from the same lots and batches as thosetested in the rabbits as noted above. The amount of sirolimus coated onthe balloon is the average sirolimus concentration based on UV-Visanalysis before pleating, folding, and sterilization of the balloons.

Formulation Sirolimus Coated on Balloons (μg) F1 64.52 ± 8.73 F1 (2^(nd)lot) 63.40 ± 2.89 F2 41.05 ± 7.17 F3  89.54 ± 19.61 F3 (2^(nd) lot)128.71 ± 26.86 F4 115.12 ± 16.92 F5 68.49 ± 4.73 F6 316.95 ± 82.66 F7165.25 ± 17.47 F8  97.19 ± 16.46 F9 218.86 ± 26.73 F10  65.38 ± 24.45F11 170.66 ± 14.30 F12  74.20 ± 15.77 F13A 134.23 ± 17.03 F13B 144.63 ±51.84 F13C  55.46 ± 13.14 F13D 105.31 ± 16.02 F14A  83.10 ± 15.19 F14B175.96 ± 78.30 F14D  77.50 ± 31.02 F15 106.53 ± 22.55 F16 75.84 ± 5.98F17 197.64 ± 15.89 F18 196.43 ± 45.89

Following expansion of the balloons in the rabbit arteries, each of theballoons was removed from the animal and the residual sirolimus on eachballoon was determined. Using the 5 minute data as an indication of theamount (and therefore percent) of sirolimus transferred to the artery,and using the amount of drug remaining on the balloon following theprocedure, and using the average amount of drug on balloons of the samebatch as an estimate of the total amount of drug on the original device(see the previous table), the percent of sirolimus transferred to therabbit artery and the total percent of sirolimus released during theentire procedure was determined. The following table summarizes theresults from the formulations tested in this manner.

Sirolimus on % Sirolimus Transferred to Balloon Post- Artery (5 min)From Sirolimus % Sirolimus Formulation Deployment (μg) Released offRespective Balloon Released F1 12.8 ± 4.0 (n = 8) 9.8 ± 3.1% (n = 8)78.9 ± 6.8% (n = 8) F1 (2^(nd) lot) 45.7 ± 7.3 (n = 36) 23.0 ± 8.5% (n =12) 35.9 ± 10.2% (n = 36) F2  6.1 ± 2.7 (n = 2) N/A 85.1 ± 3.6% (n = 2)F3 Study 1* 25.8 ± 9.6 (n = 12) N/A 68.8 ± 16.2% (n = 12) F3 Study 2*28.1 ± 4.9 (n = 6) N/A 73.1 ± 7.6% (n = 6) (2.5 μm) F3 (1^(st) lot)*27.6 ± 9.1 (n = 20) 4.8 ± 1.4% (n = 6) 68.4 ± 15.4% (n = 20) F3 (2^(nd)lot- 56.8 ± 15.6 (n = 6) 1.2 ± 0.6% (n = 2) 59.0 ± 8.6% (n = 6) 1.5 μm)*F4 16.0 ± 2.9 (n = 6) 5.1 ± 3.5% (n = 4) 84.9 ± 2.5% (n = 6) F5  5.0 ±2.7 (n = 14) 0.6 ± 0.2% (n = 4) 92.8 ± 3.7% (n = 14) F6 49.4 ± 6.9 (n =4) 3.5 ± 0.2% (n = 2) 84.4 ± 3.7% (n = 4) F7  7.1 ± 3.0 (n = 14) 3.9 ±2.4% (n = 4) 95.7 ± 1.7% (n = 14) F8 20.5 ± 0.1 (n = 2) N/A 78.1 ± 3.8%(n = 2) F9 37.0 ± 4.1 (n = 2) N/A 82.6 ± 0.3% (n = 2) F10  1.4 ± 0.8 (n= 14) 4.0 ± 0.3% (n = 4) 98.1 ± 0.8% (n = 14) F11 43.6 ± 11.2 (n = 14)1.7 ± 0.4% (n = 4) 74.4 ± 6.9% (n = 14) F12  2.3 ± 0.8 (n = 2) N/A 97.1± 1.0% (n = 2) F13A 21.6 ± 1.0 (n = 2) N/A 85.0 ± 0.8% (n = 2) F13B 30.4± 7.4 (n = 14) 3.8 ± 0.6% (n = 4) 76.5 ± 7.2% (n = 14) F13C  2.1 ± 0.1(n = 2) N/A 96.6 ± 0.0% (n = 2) F13D  9.2 ± 2.6 (n = 2) N/A 92.1 ± 2.3%(n = 2) F14A 11.6 ± 0.8 (n = 2) N/A 87.5 ± 0.3% (n = 2) F14B 16.4 ± 0.6(n = 2) N/A 91.9 ± 0.8% (n = 2) F14D  1.7 ± 0.1 (n = 2) N/A 98.5 ± 0.1%(n = 2) F15 24.9 ± 5.6 (n = 12) 5.3 ± 0.7% (n = 4) 76.4 ± 6.3% (n = 12)F16 21.4 ± 3.9 (n = 12) 4.2 ± 1.6% (n = 4) 72.0 ± 4.6% (n = 12) F17 49.3± 6.9 (n = 12) 6.6 ± 1.9% (n = 4) 74.6 ± 3.6% (n = 12) F18 44.5 ± 8.7 (n= 12) 2.5 ± 0.8% (n = 4) 76.4 ± 3.3% (n = 12) *note that several lots ofcoated balloons were manufactured and tested in several studies, and thedata presented represents data from at two studies and from at two lots.Some data is represented, thus, both in a study and also in a lotlisting in the above chart (i.e. coated balloons from manufacturing lot1 were tested in both Study 1 and Study 2, and thus the results arepresented in groups F3 Study 1, F3 Study 2, and F3 1^(st) lot above).

The following summary observations may be made with regard to the Rabbitarterial and blood testing noted in this Example. Formulation 15 has themost drug retention at 72 hours of any other formulation. Formulation 3had a sirolimus retention of 3.9+/−3.4 ng/mg at 72 hours (both lotscombined), and 3.2% of the drug released from the balloons (both lotscombined) was retained in the artery five minutes after expansion of theballoon in the artery. Formulation 13B had a sirolimus retention of0.9+/−1.7 ng/mg at 72 hours, and 3.8% of the drug released from theballoons was retained in the artery five minutes after expansion of theballoon in the artery. Formulation 15 had a sirolimus retention of46.5+/−46.1 ng/mg at 72 hours, and 5.3% of the drug released from theballoons was retained in the artery five minutes after expansion of theballoon in the artery.

Additional findings were as follows, which demonstrate for certainformulations the Tissue concentrations versus the total amount ofsirolimus per artery. Sirolimus tissue levels as an absolute amountinstead of a concentration removes experimental variability in thespecific amount of tissue harvested in the necropsy procedures.

Sirolimus Concentration Total Sirolimus per in Artery (ng/mg) Artery(μg) F3 Lot 1 (5 minutes)  45.8 ± 11.2 (n = 4)  2.6 ± 0.9 (n = 4) F3 Lot2 (5 minutes)  32.3 ± 8.0 (n = 4)  2.4 ± 2.3 (n = 4) F 13B (5 minutes) 74.2 ± 13.1 (n = 4)  2.2 ± 0.4 (n = 4) F 15 (5 minutes) 114.7 ± 66.2 (n= 4)  4.8 ± 0.6 (n = 4) F3 Lot 1 (24 h)  16.6 ± 8.5 (n = 4)  0.8 ± 0.4(n = 4) F3 Lot 2 (24 h)  31.5 ± 30.9 (n = 4)  0.8 ± 1.0 (n = 4) F 13B(24 h)  17.0 ± 13.5 (n = 4)  0.6 ± 0.3 (n = 4) F 15 (24 h) 108.2 ± 119.8(n = 4)  2.0 ± 1.9 (n = 4) F3 Lot 1 (72 h)  5.2 ± 4.2 (n = 4)  0.3 ± 0.2(n = 4) F3 Lot 2 (72 h)  3.9 ± 3.4 (n = 3)*  0.4 ± 0.5 (n = 3)* F 13B(72 h)  0.9 ± 1.7 (n = 4) 0.02 ± 0.03 (n = 4) F 15 (5 minutes)  46.5 ±46.1 (n = 4)  1.2 ± 1.1 (n = 4) *Excludes outlier of 137 ng/mg or 4.99total μg at 72 hours

In some embodiments of the methods, coatings, or devices providedherein, the coating comprises and a 10:1 ratio of the active agent tothe binding agent, wherein the active agent comprises sirolimus whereinthe binding agent comprises Polyarginine. In some embodiments, thesirolimus has an average size of 1.5 μm or 2.5 μm. In some embodiments,the Polyarginine average molecular weight is 70 kDa. In someembodiments, the Polyarginine average molecular weight is 5-15 kDa. Insome embodiments, the active agent and the binding agent are depositedon the balloon together using an eSTAT coating process. In someembodiments, the active agent and the binding agent are lyophilizedprior to deposition on the balloon. In some embodiments, at least about2 ng/mg of active agent are found in arterial tissue 72 hours afterinflation of the balloon in the artery. In some embodiments, at leastabout 3 ng/mg of active agent are found in arterial tissue 72 hoursafter inflation of the balloon in the artery. In some embodiments, atleast about 5 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 10 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 20 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 30 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 40 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery.

In some embodiments of the methods, coatings, or devices providedherein, in vivo measurement comprises inflating the balloon inside theartery of a porcine for about 1 minute and wherein the amount of activeagent transferred to the artery is measured by UV-Vis evaluation of thecoating remaining on the balloon as determined about five minutes afterinflation of the balloon in the artery. In some embodiments of themethods, coatings, or devices provided herein, in vivo measurementcomprises inflating the balloon inside the artery of a porcine for about1 minute and wherein the amount of active agent transferred to theartery is measured by extracting the artery about five minutes afterinflation of the balloon in the artery and determining the amount ofdrug in the extracted artery using standard methods described hereinand/or known to one of skill in the art. In some embodiments of themethods, coatings, or devices provided herein, in vivo measurementcomprises inflating the balloon inside the artery of a rabbit for about1 minute and wherein the amount of active agent transferred to theartery is measured by UV-Vis evaluation of the coating remaining on theballoon as determined about five minutes after inflation of the balloonin the artery. In some embodiments of the methods, coatings, or devicesprovided herein, in vivo measurement comprises inflating the ballooninside the artery of a rabbit for about 1 minute and wherein the amountof active agent transferred to the artery is measured by extracting theartery about five minutes after inflation of the balloon in the arteryand determining the amount of drug in the extracted artery usingstandard methods described herein and/or known to one of skill in theart.

Provided herein is a method of forming a coating on a medical devicecomprising depositing a polymer on the medical device using an RESSprocess, mixing a binding agent and active agent to create an activeagent-binding agent mixture, lyophilizing the active agent-binding agentmixture and depositing the active agent-binding agent mixture on themedical device using an eSTAT process. In some embodiments, the bindingagent comprises a surfactant.

Pharmacokinetic Studies in Porcine Models:

Formulation 3 (F3) was coated on balloons of 3.0×17 Ghost Rapid Exchange(Rx) Catheters according to the procedures noted above and delivered inporcine to their coronary and mammary arteries. The animals weresacrificed and arterial tissue was extracted at several time points. Theamount of drug found in the coronary arterial tissue was determined andis expressed in ng drug (Sirolimus) per mg of tissue, and is expressedin normalized form, i.e. normalized per mg of tissue and expressed inmicrograms (μg) in the following table.

Arterial Total Sirolimus Sirolimus Concentration per Artery Time Point(ng/mg) SD (μg) SD Day 1: Coronary (n = 5) 5.528 4.806 0.3647 0.3056 Day3: Coronary (n = 6) 2.559 2.927 0.1436 0.1402 Day 7: Coronary (n = 5)1.141 1.324 0.0948 0.1375 Day 14: Coronary (n = 5) 0.764 0.858 0.06450.0940 Day 30: Coronary (n = 5) 0.038 0.085 0.0013 0.0029

The amount of drug found in the mammary arterial tissue was determinedand is expressed in ng drug (Sirolimus) per mg of tissue, and isexpressed in normalized form, i.e. normalized per mg of tissue andexpressed in micrograms (μg) in the following table.

Arterial Total Sirolimus Sirolimus Concentration per Artery Time Point(ng/mg) SD (μg) SD Day 1: Mammary (n = 5) 2.722 2.931 0.1303 0.1285 Day3: Mammary (n = 4) 0.243 0.386 0.0129 0.0200 Day 7: Mammary (n = 9)0.277 0.648 0.0100 0.0225 Day 14: Mammary (n = 4) 0.105 0.066 0.00580.0037 Day 30: Mammary (n = 9) 0.030 0.090 0.0014 0.0043

A comparison was performed between arterial drug retention in a rabbitversus the porcine model, using the F3 formulation as described above.The comparison indicated that at Day 1, the Rabbit Iliac arteryconcentration of sirolimus was 25.20+/−20.20 in ng sirolimus per mgtissue, or 0.901 mg+/−0.684 mg when normalized by the amount of tissuein the sample (n=7-10). At the same time point at Day 1, the PorcineCoronary artery concentration of sirolimus was 5.528+/−4.806 in ngsirolimus per mg tissue, or 0.365 mg+/−0.306 mg when normalized by theamount of tissue in the sample (n=5-6). At Day 3, the rabbit iliacartery concentration of sirolimus was 4.66+/−3.65 in ng sirolimus per mgtissue, or 0.319 mg+/−0.338 mg when normalized by the amount of tissuein the sample. At the same time point at Day 3, the porcine coronaryartery concentration of sirolimus was 2.559+/−2.927 in ng sirolimus permg tissue, or 0.144 mg+/−0.144 mg when normalized by the amount oftissue in the sample.

Several formulations that were selected for 72-hour testing in therabbit iliac model were submitted for elution testing using a standardelution method. FIG. 1 indicates the Average percent Sirolimus Elutedfrom the balloons at various time points for Formulations F3, F5, andF7. At time 0 days, the F5 is the highest percent elution at about 60%,and the F3 elution is the next highest data point at about 45% elutionat 0 days, whereas F7 is the lowest line throughout all time points, atabout 30% eluted at 0 days. The line for F5 is the top line of thegraph, eluting the fastest of the three formulations indicated in thegraph, whereas F3 is the middle line of the graph, and F7 eluting theslowest only reaching 100% elution at about day 13.

The coating may release the active agent into a treatment site over atleast one of: about 3 days, about 5 days, about 1 week, about 1.5 weeks,about 2 weeks, about 14 days, about 3 weeks, about 21 days, about 4weeks, about 28 days, about 1 month, about 1.5 months, about 2 months,at least about 3 days, at least about 5 days, at least about 1 week, atleast about 1.5 weeks, at least about 2 weeks, at least about 14 days,at least about 3 weeks, at least about 21 days, at least about 4 weeks,at least about 28 days, at least about 1 month, at least about 1.5months, at least about 2 months, about 7 to about 14 days, about 14 toabout 21 days, about 14 to about 28 days, about 21 to about 28 days, andabout 7 to about 28 days.

Provided herein is a coated medical device comprising: a medical devicefor delivering encapsulated active agent to a treatment site; and acoating on the medical device comprising the encapsulated active agentwherein the encapsulated active agent comprise active agent encapsulatedin a polymer, and wherein the encapsulated active agent has a positivesurface charge.

Provided herein is a coated medical device comprising: a medical devicefor delivering encapsulated active agent to a treatment site; and acoating on the medical device comprising the encapsulated active agentwherein the encapsulated active agent comprise a polymer that encapsulesat least a portion of an active agent, and wherein the encapsulatedactive agent has a positive surface charge.

In some embodiments, the active agent is not completely encapsulated. Anactive agent (or a portion thereof) need not be completely surrounded inorder to be encapsulated by the polymer. In some embodiments, at least10% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 20% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 25% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 30% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 40% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 50% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 60% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 70% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 75% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 80% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 90% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 95% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast one of: at least 5% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 10% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 15% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 20% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 25% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 30% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 40% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 50% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 60% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 70% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 75% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 80% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 90% of the surface area of the active agent is atleast partially surrounded by the polymer, and at least 95% of thesurface area of the active agent is at least partially surrounded by thepolymer.

Provided herein is a coating for a medical device comprisingencapsulated active agent comprising active agent encapsulated in apolymer, wherein the encapsulated active agent has a positive surfacecharge, and wherein the coating delivers active agent to a treatmentsite over at least about 1 day.

Provided herein is a method of forming a coating on a medical devicecomprising providing encapsulated active agent comprising a polymer andactive agent, wherein the encapsulated active agent have a positivesurface charge, depositing the encapsulated active agent on the medicaldevice. In some embodiments, the coating delivers the active agent tothe treatment site over at least about 1 day.

Provided herein is a method of forming a coating on a medical devicecomprising providing encapsulated active agent comprising a polymer atleast partially encapsulating at least a portion of an active agentwherein the encapsulated active agent has a positive surface charge, anddepositing the encapsulated active agent on the medical device. In someembodiments, the coating delivers the active agent to the treatment siteover at least about 1 day.

Provided herein is a coated medical device comprising: a medical devicefor delivering an active agent to a treatment site; and a coating on thedevice comprising the active agent, wherein the coated medical devicedelivers at least a portion of the coating to the treatment site whichportion releases active agent into the treatment site over at leastabout 1 day.

Provided herein is a coating for a medical device comprising an activeagent, wherein the coating delivers the into a treatment site over atleast about 1 day.

Provided herein is a method of forming coating on a medical device withof an active agent comprising depositing the active agent on the medicaldevice using an eSTAT process.

In some embodiments of the devices, coatings and/or methods providedherein the polymer comprises PLGA. The PLGA may have at least one of: aMW of about 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDa toabout 25 KDa, and a MW of about 15 KDa to about 40 KDa.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a bioabsorbable polymer. In some embodiments, theactive agent comprises a bioabsorbable polymer. In some embodiments, thebioabsorbable polymer comprises at least one of: Polylactides (PLA);PLGA (poly(lactide-co-glycolide)); Polyanhydrides; Polyorthoesters;Poly(N-(2-hydroxypropyl) methacrylamide); DLPLA—poly(dl-lactide);LPLA—poly(l-lactide); PGA—polyglycolide; PDO—poly(dioxanone);PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(l-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(l-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations, copolymers, and derivatives thereof. In some embodiments,the bioabsorbable polymer comprises between 1% and 95% glycolic acidcontent PLGA-based polymer.

In some embodiments of the methods and/or devices provided herein, thepolymer comprises at least one of polycarboxylic acids, cellulosicpolymers, proteins, polypeptides, polyvinylpyrrolidone, maleic anhydridepolymers, polyamides, polyvinyl alcohols, polyethylene oxides,glycosaminoglycans, polysaccharides, polyesters, aliphatic polyesters,polyurethanes, polystyrenes, copolymers, silicones, silicone containingpolymers, polyalkyl siloxanes, polyorthoesters, polyanhydrides,copolymers of vinyl monomers, polycarbonates, polyethylenes,polypropytenes, polylactic acids, polylactides, polyglycolic acids,polyglycolides, polylactide-co-glycolides, polycaprolactones,poly(e-caprolactone)s, polyhydroxybutyrate valerates, polyacrylamides,polyethers, polyurethane dispersions, polyacrylates, acrylic latexdispersions, polyacrylic acid, polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, aliphatic polycarbonatespolyhydroxyalkanoates, polytetrahalooalkylenes, poly(phosphasones),polytetrahalooalkylenes, poly(phosphasones), and mixtures, combinations,and copolymers thereof. The polymers of the present invention may benatural or synthetic in origin, including gelatin, chitosan, dextrin,cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones,Poly(acrylates) such as [rho]oly(methyl methacrylate), poly(butylmethacrylate), and Poly(2-hydroxy ethyl methacrylate), Poly(vinylalcohol)Poly(olefins) such as poly(ethylene), [rho]oly(isoprene),halogenated polymers such as Poly(tetrafluoroethylene)- and derivativesand copolymers such as those commonly sold as Teflon® products,Poly(vinylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone),Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate),Poly(ethylene glycol), Poly(propylene glycol), Poly(methacrylic acid);etc. Suitable polymers also include absorbable and/or resorbablepolymers including the following, combinations, copolymers andderivatives of the following: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(l-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(l-lactide);PDO—poly(dioxanone); PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(l-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(l-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

In some embodiments of the methods and/or devices provided herein, thepolymer has a dry modulus between 3,000 and 12,000 KPa. In someembodiments, the polymer is capable of becoming soft after implantation.In some embodiments, the polymer is capable of becoming soft afterimplantation by hydration, degradation or by a combination of hydrationand degradation. In some embodiments, the polymer is adapted totransfer, free, and/or dissociate from the substrate when at theintervention site due to hydrolysis of the polymer.

In some embodiments of the methods and/or devices provided herein, thebioabsorbable polymer is capable of resorbtion in at least one of: about1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about180 days, about 6 months, about 9 months, about 1 year, about 1 to about2 days, about 1 to about 5 days, about 1 to about 2 weeks, about 2 toabout 4 weeks, about 45 to about 60 days, about 45 to about 90 days,about 30 to about 90 days, about 60 to about 90 days, about 90 to about180 days, about 60 to about 180 days, about 180 to about 365 days, about6 months to about 9 months, about 9 months to about 12 months, about 9months to about 15 months, and about 1 year to about 2 years.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a microstructure. In some embodiments, particles ofthe active agent are sequestered or encapsulated within themicrostructure. In some embodiments, the microstructure comprisesmicrochannels, micropores and/or microcavities. In some embodiments, themicrostructure is selected to allow sustained release of the activeagent. In some embodiments, the microstructure is selected to allowcontrolled release of the active agent.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a positive surface charge. The positivesurface charge may be about 20 mV to about 40 mV. The positive surfacecharge may be at least one of: at least about 1 mV, over about 1 mV, atleast about 5 mV, at least about 10 mV, about 10 mV to about 50 mV,about 20 mV to about 50 mV, about 10 mV to about 40 mV, about 30 mV toabout 40 mV, about 20 mV to about 30 mV, and about 25 mV to about 35 mV.

In some embodiments of the devices, coatings and/or methods providedherein, the w/w percent of active agent in the encapsulated active agentis about 5%. In some embodiments of the devices, coatings and/or methodsprovided herein, the w/w percent of active agent in the encapsulatedactive agent is about 10-25%.

In some embodiments, the encapsulated active agent comprises a polymerat least partially encapsulating at least a portion of an active agentwherein the encapsulated active agent has a positive surface charge. Insome embodiments, the active agent is not completely encapsulated. Anactive agent (or a portion thereof) need not be completely surrounded inorder to be encapsulated by the polymer. In some embodiments, at least10% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 20% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 25% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 30% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 40% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 50% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 60% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 70% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 75% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 80% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 90% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 95% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast one of: at least 5% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 10% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 15% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 20% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 25% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 30% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 40% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 50% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 60% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 70% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 75% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 80% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 90% of the surface area of the active agent is atleast partially surrounded by the polymer, and at least 95% of thesurface area of the active agent is at least partially surrounded by thepolymer.

In some embodiments of the devices, coatings and/or methods providedherein, at least a portion of the encapsulated active agent arenanoparticles. At least a portion of the encapsulated active agent maybe at least one of: a spherical shape, a discoidal shape, ahemispherical shape, a cylindrical shape, a conical shape, a nanoreefshape, a nanobox shape, a cluster shape, a nanotube shape, a whiskershape, a rod shape, a fiber shape, a cup shape, a jack shape, ahexagonal shape, an ellipsoid shape, an oblate ellipsoid shape, aprolate ellipsoid shape, a torus shape, a spheroid shape, a taco-likeshape, a bullet shape, a barrel shape, a lens shape, a capsule shape, apulley wheel shape, a circular disc shape, a rectangular disc shape, ahexagonal disc shape, a flying saucer-like shape, a worm shape, aribbon-like shape, and a ravioli-like shape.

The active agent in some embodiments of the devices, coatings and/ormethods provided herein comprises a macrolide immunosuppressive drug.The active agent may be selected from sirolimus, a prodrug, a hydrate,an ester, a salt, a polymorph, a derivative, and an analog thereof. Aportion of the active agent may be in crystalline form.

The active agent may be, on average, at least one of: at most 5 microns,over 1 micrometer, between 1 micrometer and 5 micrometers, about 1.5micrometers on average, and about 2.5 micrometers on average. In someembodiments, the size of the active agent in the coating is controlledin order to improve drug retention in the artery. For non-limitingexample, in the case of sirolimus as an active agent, the sirolimus mayhave an average size (mean diameter) of at least one of: 1.5 μm, 2.5 μm,645 nm, 100-200 nm, another controlled size, or a combination thereof.In some embodiments, the active agent is sirolimus and wherein thesirolimus has a median size of at least one of: 1.5 μm, 2.5 μm, 645 nm,100-200 nm, another controlled size, or a combination thereof. In someembodiments, the active agent is sirolimus and wherein the sirolimus hasan average size (mean diameter) of at least one of: about 1.5 μm, about2.5 μm, about 645 nm, about 100-200 nm, another controlled size, or acombination thereof. In some embodiments, the active agent is sirolimusand wherein the sirolimus has a median size of at least one of: about1.5 μm, about 2.5 μm, about 645 nm, about 100-200 nm, another controlledsize, or a combination thereof. In some embodiments the size of theactive agent is controlled. For example, in some embodiments, sirolimusis the active agent and at least 75% of the sirolimus as is 1.5 μm, 2.5μm, 645 nm, 100-200 nm, or another controlled size. In some embodiments,sirolimus is the active agent and at least 50% of the sirolimus as is1.5 μm, 2.5 μm, 645 nm, 100-200 nm, or another controlled size. In someembodiments, sirolimus is the active agent and at least 90% of thesirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm, or anothercontrolled size. In some embodiments, sirolimus is the active agent andat least 95% of the sirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm,or another controlled size. In some embodiments, sirolimus is the activeagent and at least 98% of the sirolimus as is 1.5 μm, 2.5 μm, 645 nm,100-200 nm, or another controlled size. In some embodiments, sirolimusis the active agent and at least 99% of the sirolimus as is 1.5 μm, 2.5μm, 645 nm, 100-200 nm, or another controlled size.

In some embodiments of the devices, coatings and/or methods providedherein the coating delivers the active agent to the treatment site overat least about 1 day. In some embodiments of the devices, coatingsand/or methods provided herein the coating delivers the active agent tothe treatment site over at least one of: about 3 days, about 5 days,about 1 week, about 1.5 weeks, about 2 weeks, about 14 days, about 3weeks, about 21 days, about 4 weeks, about 28 days, about 1 month, about1.5 months, about 2 months, at least about 3 days, at least about 5days, at least about 1 week, at least about 1.5 weeks, at least about 2weeks, at least about 14 days, at least about 3 weeks, at least about 21days, at least about 4 weeks, at least about 28 days, at least about 1month, at least about 1.5 months, at least about 2 months, about 7 toabout 14 days, about 14 to about 21 days, about 14 to about 28 days,about 21 to about 28 days, and about 7 to about 28 days.

In some embodiments of the devices, coatings and/or methods providedherein the treatment site is a vessel wall. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is acoronary artery. In some embodiments of the devices, coatings and/ormethods provided herein the treatment site is bypass graft. In someembodiments of the devices, coatings and/or methods provided herein thetreatment site is a bifurcated lesion. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is asmall coronary lesions (for example, with reference diameter<2.5 mm) Insome embodiments of the devices, coatings and/or methods provided hereinthe treatment site is a peripheral artery. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site isvein. In some embodiments of the devices, coatings and/or methodsprovided herein the treatment site is an AV graft. In some embodimentsof the devices, coatings and/or methods provided herein the treatmentsite is an AV fistula. In some embodiments of the devices, coatingsand/or methods provided herein the treatment site is a biliary tract. Insome embodiments of the devices, coatings and/or methods provided hereinthe treatment site is a biliary duct. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is asinus. In some embodiments of the devices, coatings and/or methodsprovided herein the treatment site is a vein graft.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a positive surface charge on a surface ofthe coating configured to contact the treatment site.

In some embodiments of the devices, coatings and/or methods providedherein the encapsulated active agent are micelles.

In some embodiments of the devices, coatings and/or methods providedherein the medical device comprises a balloon. In some embodiments themedical device is a balloon of a balloon catheter.

In some embodiments of the devices, coatings and/or methods providedherein depositing the encapsulated active agent comprises using an eSTATprocess. In some embodiments of the devices, coatings and/or methodsprovided herein depositing a second polymer on the medical devicefollowing depositing the encapsulated active agent on the medicaldevice.

In some embodiments of the methods, coatings or and/or devices providedherein, the coating is formed on the substrate by a process comprisingdepositing a polymer and/or the active agent by an RESS, e-RESS, ane-SEDS, or an e-DPC process. In some embodiments of the methods and/ordevices provided herein, wherein the coating is formed on the substrateby a process comprising at least one of: depositing a polymer by anRESS, e-RESS, an e-SEDS, or an e-DPC process, and depositing thepharmaceutical agent by an e-RESS, an e-SEDS, eSTAT, or an e-DPCprocess. In some embodiments of the methods and/or devices providedherein, the coating is formed on the substrate by a process comprisingat least one of: depositing a polymer by an RESS, e-RESS, an e-SEDS, oran e-DPC process, and depositing the active agent by an eSTAT, e-RESS,an e-SEDS, or an e-DPC process. In some embodiments, the process offorming the coating provides improved adherence of the coating to thesubstrate prior to deployment of the device at the intervention site andfacilitates dissociation of the coating from the substrate at theintervention site. In some embodiments, the coating is formed on thesubstrate by a process comprising depositing the active agent by aneSTAT, e-RESS, an e-SEDS, or an e-DPC process without electricallycharging the substrate. In some embodiments, the coating is formed onthe substrate by a process comprising depositing the active agent on thesubstrate by an e-RESS, an e-SEDS, or an e-DPC process without creatingan electrical potential between the substrate and a coating apparatusused to deposit the coating.

In some embodiments of the devices, coatings and/or methods providedherein the second polymer comprises PLGA. The PLGA may have at least oneof: a MW of about 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDato about 25 KDa, and a MW of about 15 KDa to about 40 KDa. Depositingthe second polymer on the medical device may use at least one of a RESScoating process, an eSTAT coating process, a dip coating process, and aspray coating process.

In some embodiments of the methods, coatings, and/or devices providedherein, the intervention site is in or on the body of a subject. In someembodiments, the intervention site is a vascular wall. In someembodiments, the intervention site is a non-vascular lumen wall. In someembodiments, the intervention site is a vascular cavity wall. In someembodiments of the methods and/or devices provided herein, theintervention site is a wall of a body cavity. In some embodiments, thebody cavity is the result of a lumpectomy. In some embodiments, theintervention site is a cannulized site within a subject. In someembodiments of the methods and/or devices provided herein, theintervention site is a sinus wall. In some embodiments, the interventionsite is a sinus cavity wall. In some embodiments, the active agentcomprises a corticosteroid.

In some embodiments of the methods, coatings, and/or devices providedherein, the coating is capable of at least one of: retarding healing,delaying healing, and preventing healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the inflammatory phase of healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the proliferative phase of healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the maturation phase of healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the remodeling phase of healing. In some embodiments, theactive agent comprises an anti-angiogenic agent.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andtransferring at least a portion of the coating from the substrate to theintervention site upon stimulating the coating with a stimulation.

Other compounds that may be used in lieu of Sirolimus (or in additionthereto) include, for non-limiting example: Sirolimus which has a FKBP12binding (nM) of 0.4-2.3 nM and an Antiproliferative potency (nM) of0.1-3.5 nM; Everolimus which has a FKBP12 binding (nM) of 1.8-2.6 nM andan Antiproliferative potency (nM) of 0.9-3.6 nM; Zotarolimus which has aFKBP12 binding (nM) of 2.0-3.2 nM and an Antiproliferative potency (nM)of 0.2-2.7 nM; Biolimus which has an Antiproliferative potency (nM) ofabout 10 nM; Temsirolimus which has a FKBP12 binding (nM) and anAntiproliferative potency (nM) that is about the same as Sirolimus;Tacrolimus which has a FKBP12 binding (nM) of 0.2-0.4 nM and anAntiproliferative potency (nM) of about 350 nM; Pimecrolimus which has aFKBP12 binding (nM) of about 1.2 nM and an Antiproliferative potency(nM) of about 1 μM.

Alternative compounds that may be used in lieu of sirolimus (or inaddition thereto) include drugs that were not sufficiently potent toeffectively deliver from a drug stent platform may be more effectivewhen delivered from a coated balloon (if the drug is highly lipophilic),for non-limiting example: Dipyradamole, Cerivastatin, Troglitazone,and/or Cilostazol. Dipyradamole may be an appropriate drug for use on acoating of a balloon, for example, since it inhibits VSMC (vascularsmooth muscle cell) proliferation, is anti-inflammatory, improvesendothelial function, and provides local release of t-PA (tissueplasminogen activator). Cerivastatin may be an appropriate drug for useon a coating of a balloon, for example, since it inhibits VSMCproliferation, is anti-inflammatory, improves endothelial function, andcan stabilize vulnerable plaque. Troglitazone may be an appropriate drugfor use on a coating of a balloon, for example, since it inhibits VSMCproliferation, is anti-inflammatory, improves endothelial function, andmay provide vascular lipid reduction. Cilostazol may be an appropriatedrug for use on a coating of a balloon, for example, since it inhibitsVSMC proliferation, may be anti-inflammatory, improves endothelialfunction, and is a vasodilator and/or increases NO (nitric oxide)release and/or production of NO.

Other drugs that may be appropriate for use on a drug balloon as acoating that is released thereby include the following: Drugs to preventelastic recoil such as smooth muscle cell relaxants and/or agents thatbind elastin; Drugs to prevent reperfusion injury such as ANP,atorvastatin, erythropoietin, and/or glucagon-like peptide 1; Drugs tostimulate collateral blood flow such as Vasodilators and/or Growthfactors (GF) and GF activators. Drug coated balloons may be useful inlower extremities and in peripheral indications, such as in PTA(Percutaneous transluminal angioplasty) and in combination with a barestent, in situations of in stent restenosis, following atherectomy. Drugcoated balloons may be particularly useful in certain coronaryindications, such as following in stent restenosis, in small vesselangioplasty situations, in bifurcations, and in combination with a baremetal stent. Other uses include in AV Fistulae and Grafts (dialysis), inthe nasal sinus, in neurovascular vessels, in renal vessels orapplications, in anti-cancer applications, and in urologicalapplications. a) Fistulae and Grafts (dialysis) Fistulae and Grafts(dialysis) Fistulae and Grafts (dialysis).

In some embodiments, the device releases at least 3% of the active agentto artery in vivo. In some embodiments, the device releases at least 5%of the active agent to artery in vivo. In some embodiments, the devicereleases at least 10% of the active agent in vivo. In some embodiments,the device releases at least 5% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 7% of the active agent to artery upon inflation of theballoon in vivo. In some embodiments, the device releases at least 10%of the active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases at least 15% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 20% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 25% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least30% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 40% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 50% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases between 2% and 50% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 50% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between5% and 50% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 30% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 25% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 20% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 3% and 15% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 1% and 15% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between1% and 10% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 10% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 1% and 5% of the activeagent to artery upon inflation of the balloon in vivo.

As used herein, depending on the embodiment, “upon inflation” means assoon as reasonably possible following removal of the device from thetreatment site. This may include timings such as about 1 minute, about 5minutes from removal of the device from the treatment site, within 1 to15 minutes from the removal of the device from the treatment site,within 1 to 15 minutes from the removal of the device from the treatmentsite, within 1 to 20 minutes from the removal of the device from thetreatment site, within 1 minute to 1 hour from the removal of the devicefrom the treatment site, within 1 minute to 2 hour from the removal ofthe device from the treatment site, and/or within 1 minute to 3 hoursfrom the removal of the device from the treatment site.

Example 5 Delivery of Rapamycin from Coated Invertable Balloons

Provided herein is a device comprising an invertable balloon, a coatingon the abluminal side of the invertable balloon, wherein the coatingcomprises an active agent and a binding agent. In some embodiments, thedevice releases at least 3% of the active agent to artery upon inflationof the balloon in vivo.

In some embodiments, the device releases at least 5% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 7% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 10% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least15% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 20% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 25% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 30% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 40% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least50% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases between 2% and 50% of theactive agent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 50% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 5% and 50% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 30% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between3% and 25% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 20% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 15% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1% and 15% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 1% and 10% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 10% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between1% and 5% of the active agent to artery upon inflation of the balloon invivo.

Example invertable balloons (which may also and/or alternatively becalled evertable balloons) include, but are not limited to, thosedescribed in U.S. Pat. No. 6,039,721 filed Dec. 3, 1997; and U.S. Pat.No. 4,606,347 filed Aug. 8, 1985 which patents are incorporated hereinby reference in their entirety. In some embodiments the abluminalsurface of the balloon is coated prior to inversion, and once coated,the balloon is inverted such that the abluminal surface of the balloonis protected from either blood flow during tracking or tracking contactwith the vessel wall, or both, until the balloon catheter is positionednear the treatment site, usually just proximally to the site. As usedherein, “abluminal side” or “abluminal surface” refers to a portion ofthe balloon having coating thereon, and intended to deliver the coating(agent) to the treatment site or location—i.e. the lumen of the vesselin the case of a treatment site that is a vessel. The balloon is thenun-inverted such that the abluminal surface is positioned within thetreatment site.

In an embodiment wherein the balloon is inverted within a catheter, itmay be pushed out of the catheter using either pressure from theindeflator or another form of un-inversion of the balloon, such as fornonlimiting example, by moving the distal end of the balloon distallythrough the balloon itself, essentially unrolling the balloon into thetreatment site such that the coated portion of the balloon is adjacentthe treatment site. In certain embodiments where the balloon in invertedon the outside of the catheter, a similar movement and/or pressure fromthe indeflator can move the distal end of the balloon distally therebyunrolling the coated side of the balloon into proximity of the treatmentsite. In some embodiments, the balloon may be partially un-inverted,such that the treatment length may be controlled. The balloon thereafteris inflated such that the abluminal surface that is coated contactsand/or dilates the treatment site, thereby delivering the coating or aportion thereof to the treatment site.

Any of the devices, coatings, and/or methods described herein may becombined with an inverteable type of balloon to deliver the coating in amanner that reduces and/or substantially eliminates loss of coating dueto tracking and/or blood flow and/or other in-transit coating loss priorto locating the device at the treatment site (i.e. delivering the deviceto the treatment site). In some embodiments, at most 1% of coating isremoved from the balloon due to tracking of the coated balloon to thetreatment site. In some embodiments, at most 3% of coating is removedfrom the balloon due to tracking of the coated balloon to the treatmentsite. In some embodiments, at most 5% of coating is removed from theballoon due to tracking of the coated balloon to the treatment site. Insome embodiments, at most 10% of coating is removed from the balloon dueto tracking of the coated balloon to the treatment site. In someembodiments, at most 15% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 20% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 25% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 30% of coating is removed from the balloon due totracking of the coated balloon to the treatment site.

As used herein, depending on the embodiment, “upon inflation” means assoon as reasonably possible following removal of the device from thetreatment site. This may include timings such as about 1 minute, about 5minutes from removal of the device from the treatment site, within 1 to15 minutes from the removal of the device from the treatment site,within 1 to 15 minutes from the removal of the device from the treatmentsite, within 1 to 20 minutes from the removal of the device from thetreatment site, within 1 minute to 1 hour from the removal of the devicefrom the treatment site, within 1 minute to 2 hour from the removal ofthe device from the treatment site, and/or within 1 minute to 3 hoursfrom the removal of the device from the treatment site.

Example 6 Delivery of Rapamycin from Sheathed Coated Balloons

Provided herein is a device comprising an balloon, a coating on theabluminal side of the balloon, and a sheath over the balloon, whereinthe coating comprises an active agent and a binding agent. In someembodiments, the device releases at least 3% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thesheath may be retracted. In some embodiments, the sheath may beretracted to expose the coating to the treatment site. In someembodiments, the sheath covers the coated balloon until the balloonreaches the treatment site. In some embodiments the sheath may beretracted once the coated balloon is positioned near and/or at thetreatment site. In some embodiments, the sheath covers the coatedballoon until the balloon is proximal to the treatment site. In someembodiments, the sheath covers the coated balloon until the balloon isdistal to the treatment site. In some embodiments, the sheath covers thecoated balloon until the balloon is within to the treatment site. Insome embodiments, the sheath may be moved over the balloon followingdeflation of the balloon after the coating (or a portion thereof) hasbeen released to the artery, and the catheter may be removed such thatthe coated balloon is covered during removal from the subject. In someembodiments, the sheath may remain in a retracted state followingdeflation of the balloon after the coating (or a portion thereof) hasbeen released to the artery, and the catheter may be removed such thatthe coated balloon is exposed to the delivery track during removal fromthe subject.

Any of the devices, coatings, and/or methods described herein may becombined with a sheath to deliver the coating in a manner that reducesand/or substantially eliminates loss of coating due to tracking and/orblood flow and/or other in-transit coating loss prior to locating thedevice at the treatment site (i.e. delivering the device to thetreatment site). In some embodiments, at most 1% of coating is removedfrom the balloon due to tracking of the coated balloon to the treatmentsite. In some embodiments, at most 3% of coating is removed from theballoon due to tracking of the coated balloon to the treatment site. Insome embodiments, at most 5% of coating is removed from the balloon dueto tracking of the coated balloon to the treatment site. In someembodiments, at most 10% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 15% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 20% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 25% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 30% of coating is removed from the balloon due totracking of the coated balloon to the treatment site.

In some embodiments, the device releases at least 5% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 7% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 10% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least15% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 20% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 25% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 30% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 40% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least50% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases between 2% and 50% of theactive agent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 50% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 5% and 50% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 30% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between3% and 25% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 20% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 15% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1% and 15% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 1% and 10% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 10% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between1% and 5% of the active agent to artery upon inflation of the balloon invivo.

As used herein, depending on the embodiment, “upon inflation” means assoon as reasonably possible following removal of the device from thetreatment site. This may include timings such as about 1 minute, about 5minutes from removal of the device from the treatment site, within 1 to15 minutes from the removal of the device from the treatment site,within 1 to 15 minutes from the removal of the device from the treatmentsite, within 1 to 20 minutes from the removal of the device from thetreatment site, within 1 minute to 1 hour from the removal of the devicefrom the treatment site, within 1 minute to 2 hour from the removal ofthe device from the treatment site, and/or within 1 minute to 3 hoursfrom the removal of the device from the treatment site.

Example 7 Delivery of Rapamycin from Coated Balloons with Occluder

Provided herein is a device comprising a balloon, a coating on theballoon, and an occluder, wherein the coating comprises an active agentand a binding agent. In some embodiments, the occluder is a flowoccluder configured to block the flow of bodily fluids (e.g. blood) atthe treatment site during exposure of the coating to the treatment site.In some embodiments, the device releases at least 3% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the occluder comprises a second balloon that occludes the flow of theblood at the treatment site. In some embodiments, the balloon comprisesthe occluder, such that the balloon has two sections the flow occluderand the coated portion, wherein the flow occluder occludes the flow ofthe blood at the treatment site. In some embodiments, the balloon isdual-noded, wherein the distal node is coated and wherein the proximalnode is the occluder. In some embodiments, the occluder is locatedproximally from the balloon, and/or portion thereof, having coatingthereon. In some embodiments, the balloon is dual-noded, wherein theproximal node is coated and wherein the distal node is the occluder. Insome embodiments the occluder is located distally from the balloon,and/or portion thereof, having coating thereon. In some embodiments, theballoon is a shape appropriate for the treatment site, such that theoccluder portion of the balloon is the appropriate shape to occlude flowof blood at the treatment site. In some embodiments, the occludersubstantially conforms to the shape of a treatment area near thetreatment site such blood flow at the treatment site is occludedthereby. In some embodiments, the balloon is only partially coated, suchthat either or both the distal and proximal end of the balloon is notcoated, and the distal and/or proximal end of the balloon is theoccluder.

Provided herein is a device comprising a first balloon, a coating on thefirst balloon, and a second balloon capable of occluding flow of bloodat the treatment site during expansion of the first balloon at thetreatment site. In some embodiments, the occluder is a second balloonwhich is not the balloon having coating thereon. In some embodiments,the occluder is located proximally from the balloon, and/or portionthereof, having coating thereon. In some embodiments the occluder islocated distally from the balloon, and/or portion thereof, havingcoating thereon.

Provided herein is a device comprising a first balloon, a coating on thefirst balloon, and a second balloon configured such that the secondballoon expands prior to expansion of the first balloon. In someembodiments the occluder occludes the flow of the blood at the treatmentprior to expansion of the portion of the balloon. In some embodiments,the occluder is located proximally from the balloon, and/or portionthereof, having coating thereon. In some embodiments the occluder islocated distally from the balloon, and/or portion thereof, havingcoating thereon.

In some embodiments, the occluder is not a balloon, but is another formof occluder that is configured to occlude flow of blood at the treatmentsite. In some embodiments, the occluder is deployable and retractable,such that it can be deployed prior to inflation of the balloon havingcoating thereon, and following balloon inflation and delivery of theagent to the treatment site, the occluder can be retracted and removedeither with the removal of the balloon, or following removal of theballoon from the treatment site.

In some embodiments, the occluder has a second coating thereon, having asecond agent and/or polymer coated thereon as described elsewhereherein, according to any of the methods and processes as noted herein.The second coating in some embodiments comprises a binding agent. Thesecond coating in some embodiments does not comprise a binding agent.

In some embodiments, the device releases at least 5% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 7% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 10% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least15% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 20% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 25% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 30% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 40% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least50% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases between 2% and 50% of theactive agent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 50% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 5% and 50% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 30% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between3% and 25% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 20% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 15% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1% and 15% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 1% and 10% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 10% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between1% and 5% of the active agent to artery upon inflation of the balloon invivo.

Example 8 Coatings Prepared with and without Shear Mixing

F15 (Formulation 15) as described in Example 4 was produced in multiplelots and having various rapamycin:polyarginine ratios. Regardless of therapamycin:polyarginine ratio, however, indicative of F15 is that itcomprises PLGA i.e. about 50:50 Lactic acid:Glycolic acid, Sirolimushaving an average size of 1.5 μm, and Polyarginine 5-15 kDa. Thesirolimus was in crystalline form. The following Rapamycin:PolyarginineRatios were produced for this Example: 1:1, 5:1, 10:1, and 50:1.

In some lots (generally called F15 Lot 3 1:1, 5:1, 10:1, or 50:1), theproduction method for the formulation was as depicted in FIG. 4. Themethod for these lots was as follows: Dissolve 25 mg Poly-L-argininehydrochloride (Aldrich P4663) (also called polyarginine herein) (cas26982-20-7, 5-15 kDa) in 50 ml deionized water in 100 ml bottle and add250 mg encapsulated rapamycin (1.5 micron particle size, crystallineform) (step 46). Sonicate (Branson 1510 bench top ultrasonic cleaner)for 2 h (step 48). Manually separate well-suspended liquid portion fromunsuspended solids using pipette (step 50). Centrifuge˜50 ml suspensionfor 30 min at 10,000 rpm (ThermoElectronCorp. IEC Multi RF Centrifuge)(step 52). Decant supernatant without allowing sediment to come todryness (step 54). There will be an amount of unsuspended fraction 64following centrifuge step 52. Add aqueous solution of poly-L-argininehydrochloride concentration to produce desired encapsulatedSirolimus/poly-L-arginine hydrochloride ratio (step 56). Re-suspendsediment by shaking and 10 minute sonication. Lyophilize suspension toproduce un-agglomerated encapsulated rapamycin/polyarginine powder solidlyophilisate 66 (Flexi-Dry MP) (step 58). This step took two to threedays to achieve completion. This lyophilized solid 66 was eSTAT coatedonto a balloon or a PLGA-coated balloons as a powder (dry coating asdescribed herein) (step 60) to produce a coated balloon 62 comprisingPLGA, rapamycin, and polyarginine, wherein the rapamycin is crystallinein form.

For the ratio-forming step, the ratios were produced as follows: 95 mlMasterbatch (combination of “well-suspended” portions of 4 sonicatedsolutions), estimated to be ˜5 mg/ml solids, was divided into 5portions. For the 50:1 ratio of sirolimus to polyarginine, 20 ml waterwas added to the first 18 ml portion, it was sonicated to re-suspend andlyophilized to produce 50.3 mg solid lyophilisate. For the 10:1 ratio ofsirolimus to polyarginine, 9 mg polyarginine was dissolved in 20 mlwater and was added to the second 18 ml portion whis was sonicated tore-suspend and lyophilized to produce 116.6 mg solid lyophilisate. Forthe 5:1 ratio of sirolimus to polyarginine, 18 mg polyarginine wasdissolved in 20 ml water and was added to the third 18 ml portion, itwas sonicated to re-suspend and lyophilized to produce 127.4 mg solidlyophilisate. For the 1:1 ratio of sirolimus to polyarginine, 90 mgpolyarginine was dissolved in 20 ml water and was added to the fourth 18ml portion, it was sonicated to re-suspend and lyophilized to produce142.4 mg solid lyophilisate.

In some lots (generally called F15 Lot 4 5:1 or 10:1), the productionmethods for a F15 formulation having a 5:1 ratio of rapamycin topolyarginine lot and a F15 formulation having a 10:1 ratio of rapamycinto polyarginine lot were as follows. Dissolve 25 mg (10:1) or 50 mg(5:1) Poly-L-arginine hydrochloride (Aldrich P4663) (cas 26982-20-7)(5-15 kDa) (also called polyarginine) in 25 ml deionized water in 20 mlvial. Add 250 mg Sirolimus (1.5 micron particle size, crystalline inform). Mix for 10 min at 10,000 rpm in Laboratory Mixer (Silverson L4RT)using micro mixer head attachment to form a suspension (this mixingleaves little or no sediment). The Lab Mixer is a High Shear Mixerhaving an impeller for mechanical mixing. Run mixer with 25 ml purewater to recover residual material (rinse water). Combine suspensionwith rinse water. Lyophilize suspension to produce un-agglomeratedSirolimus/polyarginine powder (Flexi-Dry MP), which took two to threedays to achieve completion. This lyophilized solid 66 was eSTAT coatedonto PLGA coated balloons as a powder (dry coating as described herein)to produce a coated balloon comprising PLGA, rapamycin, andpolyarginine, wherein the rapamycin is crystalline in form.

The amount of rapamycin that was found in the actual coated balloon wasalso determined and could be used to determine an actualrapamycin:polyarginine ratio (as opposed to the target ratio provided asnoted elsewhere herein). To measure the amount of sirolimus onindividual balloons ultraviolet-visible spectroscopy (UV-Vis) wasemployed. After sintering, coated balloons are cut (the stylus isremoved before cutting) from the catheter wires leaving only ˜¼″ of thewires remaining connected to the balloons. Balloons were placed inindividual 5 ml scintillation vials containing 4 ml of ethanol ormethanol (sirolimus is soluble in ethanol up to 50 mg/ml). Sonicationfor 3 h removes sirolimus from the balloons. Following sonication UV-Visis performed. Due to sirolimus being a triene (containing three doublebonds) it produces UV absorbance at 3 wavelengths: 1 major peak at 277nm and two smaller peaks at 267 nm and 288 nm. Uncoated GHOST rapidexchange nylon balloons and PLGA have also been individually sonicatedfor 3 h in ethanol and showed no interfering extractives for sirolimusmeasurements. The absorbance of sirolimus subtracted from the absorbanceof an uncoated balloon at 277 nm is used in conjunction with a standardcurve to calculate the amount of sirolimus per coated balloon. Astandard of 3 from a batch of 12 coated balloons underwent UV-Visanalysis to obtain a batch average of sirolimus per balloon (measured inμg). The UV-Vis analysis could also be used to determine the presenceand/or quantitate the amount of polymer (in this Example, PLGA) in thecoating. UV-Vis testing of both lots 3 and 4 revealed presence of bothpolyarginine and rapamycin on the coated balloons. For Lot 3, thefollowing actual ratios were determined: for Lot 3 1:1 (ideal) actualwas about 1.3:1, for Lot 3 5:1 (ideal) actual was about 7.1:1, Lot 310:1 (ideal) actual was about 14.3:1, for Lot 3 50:1 (ideal) actual wasabout 43.1:1. Likewise, for Lot 4 5:1 (ideal) actual was about 6.1:1.

F15 Lot 3 coated balloons were delivered to arteries of animals of arabbit study to assess if and how much of the rapamycin was retained inrabbit iliac arteries for 72 hours. The following coated balloonformulations were as follows in Table 18.

TABLE 18 Sirolimus:Polyarginine Sirolimus/Balloon Ratio (μg) (n = 6)*Coating Appearance  1:1 65.37 ± 3.84 Transparent, Speckled  5:1 79.02 ±9.83 Translucent, Very Thick 10:1 89.71 ± 5.27 Translucent, Very Thick50:1 81.28 ± 4.61 Translucent, Very Thick *Average Sirolimusconcentrations based on UV-Vis analysis before pleating/folding andsterilization of balloons.

Study design for this study was as depicted in Table 19.

TABLE 19 Number of Blood Vessels PK Per Necropsy Time Test ArticleAnimals Per Animal Animal Points F15 Sirolimus: n = 3 n = 2 denuded n =2 time 3 days (±5%) Polyarginine per ratio rabbit iliac points Ratios:1:1, 5:1, arteries (baseline/ 10:1, 50:1 before necropsy) Totals 12 2424 3 days (±5%) Deployed balloons, blood samples and denuded iliacarteries analyzed for Sirolimus levels.

The following results were determined as shown in Tables 20, 21, 22.Most retention from 10:1 ratio of F15 Lot 3 (1.8±1.2 ng/mg). Sirolimusblood levels below 1 ng/ml by 3 days.

TABLE 20 Arterial Total Sirolimus Sirolimus Concentration per Artery F15Ratio (ng/mg) SD (μg) SD F15 1:1 Lot 3, n = 6 1.52 2.63 0.022 0.035 F155:1 Lot 3, n = 6 0.67 0.53 0.013 0.011 F15 10:1 Lot 3, n = 6 1.77 1.180.041 0.030 F15 50:1 Lot 3, n = 6 0.63 0.18 0.010 0.003

TABLE 21 Sirolimus Concentration on % Sirolimus 4F15 Ratio Balloon AfterDeployment (ug) Released/Lost*  1:1 Lot 3 20.6 ± 9.8 (n = 6) 68.9 ±14.0% (n = 6)   5:1 Lot 3 37.9 ± 6.3 (n = 6) 52.0 ± 7.8% (n = 6) 10:1Lot 3 41.3 ± 7.2 (n = 6) 53.7 ± 9.1% (n = 6) 50:1 Lot 3 45.4 ± 6.9 (n =6) 44.2 ± 8.6% (n = 6) *Based on Balloon Batch Averages of Sirolimus

The amount of Sirolimus coated on balloons was as follows: F15 (1:1, Lot3) Sirolimus coated on balloons=65.37±3.84; F15 (5:1, Lot 3) Sirolimuscoated on balloons=79.02±9.83; F15 (10:1, Lot 3) Sirolimus coated onballoons=89.71±5.27; F15 (50:1, Lot 3) Sirolimus coated onballoons=81.28±4.61.

TABLE 22 Sirolimus Concentration in Est. Total F15 Ratio Whole Blood(ng/mL) Sirolimus in Blood (μg)*  1:1 Lot 3 0.29 ± 0.03 (n = 3) 0.054 ±0.01 (n = 3)  5:1 Lot 3 0.50 ± 0.15 (n = 3) 0.096 ± 0.03 (n = 3) 10:1Lot 3 0.43 ± 0.12 (n = 3) 0.081 ± 0.02 (n = 3) 50:1 Lot 3 0.38 ± 0.08 (n= 3) 0.064 ± 0.01 (n = 3) *Based on 56 mL Blood per kg; BQL = belowquantitation limit (0.1 ng/ml)

F15 Lot 4 coated balloons were delivered to arteries of animals of arabbit study to assess if and how much of the rapamycin was retained inrabbit iliac arteries for 72 hours.

Provided herein is a method of coating at least a portion of a medicaldevice comprising a balloon, thereby forming on the medical device acoating on the balloon comprising an active agent and a binding agent,wherein the method comprises: dissolving the binding agent to form abinding agent solution, combining the binding agent solution and theactive agent, mixing the combined binding agent and active agent using ahigh shear mixer, forming a suspension comprising the combined mixedactive agent and binding agent, lyophilising the suspension to form alyophilisate of the active agent and the binding agent, and coating theballoon with the lyophilisate in powder form using an eSTAT process,wherein the active agent coated on the balloon comprises active agent incrystalline form.

In some embodiments, the high shear mixer is a mechanical mixer. In someembodiments, the mechanical mixer comprises an impeller, propeller,and/or a high speed saw tooth disperser. In some embodiments, themechanical mixer comprise a high pressure pump. In some embodiments, thehigh shear mixer comprises a sonic mixer. In some embodiments, the sonicmixer comprises a sonicator. In some embodiments, the sonic mixercomprises a benchtop bath based sonicator. In some embodiments, thesonic mixer comprises an ultrasonic mixer. In some embodiments, thesonic mixer comprises an megasonic mixer.

In some embodiments, the mechanical mixer comprise a high pressure pump(up to 40,000 psi (2578 bar)) that forces particles into an interactionchamber at speeds up to 400 m/s. The interaction chamber may compriseengineered microchannels. Inside the chamber, the product may be exposedto consistent impact and shear forces and then cooled.

A high shear mixer disperses, or transports, one phase or ingredient(liquid, solid, gas) into a main continuous phase (liquid), with whichit would normally be immiscible. In some embodiments of a mechanicalmixer that is a high shear mixer, a rotor or impellor, together with astationary component known as a stator, or an array of rotors andstators, is used either in a tank containing the solution to be mixed,or in a pipe through which the solution passes, to create shear. A highshear mixer can be used to create emulsions, suspensions, lyosols (gasdispersed in liquid), and granular products.

Fluid undergoes shear when one area of fluid travels with a differentvelocity relative to an adjacent area. In some embodiments of amechanical mixer that is a high shear mixer, the high shear mixer uses arotating impeller or high-speed rotor, or a series of such impellers orinline rotors, usually powered by an electric motor, to “work” thefluid, creating flow and shear. The tip velocity, or speed of the fluidat the outside diameter of the rotor, will be higher than the velocityat the centre of the rotor, and it is this velocity difference thatcreates shear.

A stationary component may be used in combination with the rotor, and isreferred to as the stator. The stator creates a close-clearance gapbetween the rotor and itself and forms an extremely high shear zone forthe material as it exits the rotor. The rotor and stator combinedtogether are often referred to as the mixing head, or generator. A largehigh shear rotor-stator mixer may contain a number of generators.

In some embodiments the mechanical mixer comprises a batch high shearmixer. In a batch high shear mixer, the components to be mixed (whetherimmiscible liquids or powder in liquid) are fed from the top into amixing tank containing the mixer on a rotating shaft at the bottom ofthe tank. A batch high shear mixer can process a given volume ofmaterial approximately twice as fast as an inline rotor-stator mixer ofthe same power rating; such mixers continue to be used where fasterprocessing by volume is the major requirement, and space is not limited.When mixing sticky solutions, some of the product may be left in thetank, necessitating cleaning. However, there are designs of batch highshear mixers that clean the tank as part of the operating run. Some highshear mixers are designed to run dry, limiting the amount of cleaningneeded in the tank.

In some embodiments the mechanical mixer comprises an inline high shearrotor-stator mixer. Generally speaking this version takes the same rotorand stator from the batch high shear mixer and installs it in a housingwith inlet and outlet connections. Then the rotor is driven through ashaft seal thus resulting in a rotor-stator mixer that behaves like acentrifugal pumping device. That is, in an inline high shearrotor-stator mixer, the rotor-stator array is contained in a housingwith an inlet at one end and an outlet at the other, and the rotordriven through a seal. The components to be mixed are drawn through thegenerator array in a continuous stream, with the whole acting as acentrifugal pumping device. Inline high shear mixers offer a morecontrolled mixing environment, take up less space, and can be used aspart of a continuous process. Equilibrium mixing can be achieved bypassing the product through the inline high shear mixer more than once.Since the inline mixer may be positioned in a flowing stream, the mixingmay be more controlled than in a batch configuration, so the number ofpasses through the high shear zone can be monitored.

An inline rotor-stator mixer equipped for powder induction offersflexibility, capability, and portability to serve multiple mix vesselsof virtually any size. Its straightforward operation and conveniencefurther maximize equipment utility while simplifying material handling.

When used with a vacuum pump and hopper, an inline shear mixer can be avery effective way to incorporate powders into liquid streams. Otherwiseknown as high shear powder inductors, these systems have the advantageof keeping the process on the floor level instead of working with heavybags on mezzanines. High shear powder induction systems also offer easyinterchangeability with multiple tanks.

A high shear granulator is a process array consisting of an inline orbatch high shear mixer and a fluid-bed dryer. In a granulation process,only the solid component of the mixture is required. Fluid is used onlyas an aid to processing. The high shear mixer processes the solidmaterial down to the desired particle size, and the mixture is thenpumped to the drying bed where the fluid is removed, leaving behind thegranular product.

In an ultra-high shear inline mixer, the high shear mixing takes placein a single or multiple passes through a rotor-stator array. The mixeris designed to subject the product to higher shear and a larger numberof shearing events than a standard inline rotor-stator mixer, producingan exceptionally narrow particle-size distribution. Sub-micrometreparticle sizes are possible using the ultra-high shear technology. Toachieve this, the machine is equipped with stators withprecision-machined holes or slots through which the product is forced bythe rotors. The rotor-stator array can also include a mechanism wherebythe momentum of the flow is changed (for example by forcing it sidewaysthrough the stator), allowing for more processing in a single pass.

High shear mixers may be used to produce standard mixtures ofingredients that do not naturally mix. When the total fluid is composedof two or more liquids, the final result is an emulsion; when composedof a solid and a liquid, it is termed a suspension and when a gas isdispersed throughout a liquid, the result is a lyosol. Each class may ormay not be homogenized, depending on the amount of input energy.

To achieve a standard mix, the technique of equilibrium mixing may beused. A target characteristic is identified, such that once the mixedproduct has acquired that characteristic, it will not changesignificantly thereafter, no matter how long the product is processed.For dispersions, this is the equilibrium particle size. For emulsions,it is the equilibrium droplet size. The amount of mixing required toachieve equilibrium mixing is measured in tank turnover—the number oftimes the volume of material must pass through the high shear zone.

In some embodiments, the sonic mixer comprises a sonicator. In someembodiments, the sonic mixer comprises a benchtop bath based sonicator.In some embodiments, the sonic mixer comprises an ultrasonic mixer. Theultrasonic mixer may employ ultrasonic frequencies of any one or moreof: about 18 kHz at least, about 20 kHz at least, less than 400 kHz,less than 500 kHz, about 18 kHz to about 400 kHz, about 20 kHz to about500 kHz, at most about 400 kHz, and at most about 500 kHz. In someembodiments, the sonic mixer comprises an megasonic mixer. The megasonicmixer may employ megasonic frequencies of any one or more of: about 500kHz at least, about 700 kHz at least, about 800 kHz at least, less thanabout 5 MHz, less than about 4 MHz, about 500 kHz to about 5 MHz, about700 kHz to about 4 MHz, at most about 5 MHz, at most about 4 MHz, atleast about 1 MHz, and any frequency in the MHz range.

In some embodiments, a ratio of the active agent to the binding agent is1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:20, 2:1, 3:1, 4:1, 5:1, 10:1, 15:1,20:1, 3:2, 2:3, 5:2, 5:3, 2:5, or 3:5 as a target ratio. In someembodiments, the actual ratio of the active agent to the binding agentis +/−10% of the ideal ratio, +/−20% of the ideal ratio, +/−25% of theideal ratio, or +/−30% of the target ratio. In some embodiments, theactual ratio is calculated based on UV-Vis testing of the medicaldevice.

In some embodiments when the balloon of the device is delivered to anartery in vivo, at least 3% of the active agent is transferred to tissueof the artery. In some embodiments, at least 5% of the active agent istransferred to tissue of the artery. In some embodiments, at least 10%of the active agent is transferred to tissue of the artery.

In some embodiments, the binding agents comprises at least one of:Polyarginine, Polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethylcellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI(Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB(Dimethylditetradecylammonium bromide).

In some embodiments, an average molecular weight of the binding agent iscontrolled. In some embodiments, a size of the active agent in thecoating is controlled.

In some embodiments, the active agent is sirolimus and wherein thesirolimus has have an average size of at least one of: about 1.5 μm,about 2.5 μm, about 645 nm, about 100-200 nm, another controlled size,or a combination thereof. In some embodiments, the active agent issirolimus and wherein sirolimus at least 75% of the sirolimus as is 1.5μm, 2.5 μm, 645 nm, 100-200 nm, or another controlled size. In someembodiments, the active agent is sirolimus and wherein sirolimus atleast 50% of the sirolimus as is 1.5 μm, 2.5 μm, 645 nm, 100-200 nm, oranother controlled size. In some embodiments, the active agent issirolimus and wherein sirolimus at least 90% of the sirolimus as is 1.5μm, 2.5 μm, 645 nm, 100-200 nm, or another controlled size. In someembodiments, the coating may comprise nanoparticles, and thenanoparticles may comprise an active agent and a polymer.

In some embodiments, the coating comprises PLGA comprising about 50:50Lactic acid:Glycolic acid. In some embodiments, the coating comprisedand about a 10:1 ratio of the active agent to the binding agent, whereinthe active agent comprises sirolimus wherein the binding agent comprisesPolyarginine. In some embodiments, the sirolimus has an average size of1.5 μm or 2.5 μm. In some embodiments, the Polyarginine averagemolecular weight is 70 kDa. In some embodiments, the Polyarginineaverage molecular weight is 5-15 kDa. In some embodiments, the activeagent and the binding agent are lyophilized prior to deposition on theballoon. In some embodiments, at least about 2 ng/mg of active agent, atleast about 3 ng/mg of active agent, at least about 5 ng/mg of activeagent, at least about 10 ng/mg of active agent, at least about 20 ng/mgof active agent, at least about 30 ng/mg of active agent, and/or atleast about 40 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery.

In some embodiments, in vivo measurement comprises inflating the ballooninside the artery of a porcine for about 1 minute and the amount ofactive agent transferred to the artery is measured by UV-Vis evaluationof the coating remaining on the balloon as determined five minutes afterinflation of the balloon in the artery. In some embodiments, in vivomeasurement comprises inflating the balloon inside the artery of arabbit for about 1 minute and the amount of active agent transferred tothe artery is measured by UV-Vis evaluation of the coating remaining onthe balloon as determined five

In some embodiments, the device releases at least one of: at least 5% ofthe active agent to artery upon inflation of the balloon in vivo, atleast 7% of the active agent to artery upon inflation of the balloon invivo, at least 10% of the active agent to artery upon inflation of theballoon in vivo, at least 15% of the active agent to artery uponinflation of the balloon in vivo, at least 20% of the active agent toartery upon inflation of the balloon in vivo, at least 25% of the activeagent to artery upon inflation of the balloon in vivo, at least 25% ofthe active agent to artery upon inflation of the balloon in vivo, atleast 30% of the active agent to artery upon inflation of the balloon invivo, at least 40% of the active agent to artery upon inflation of theballoon in vivo, at least 50% of the active agent to artery uponinflation of the balloon in vivo, between 2% and 50% of the active agentto artery upon inflation of the balloon in vivo, between 3% and 50% ofthe active agent to artery upon inflation of the balloon in vivo,between 5% and 50% of the active agent to artery upon inflation of theballoon in vivo, between 3% and 30% of the active agent to artery uponinflation of the balloon in vivo, between 3% and 25% of the active agentto artery upon inflation of the balloon in vivo, between 3% and 20% ofthe active agent to artery upon inflation of the balloon in vivo,between 3% and 15% of the active agent to artery upon inflation of theballoon in vivo, between 1% and 15% of the active agent to artery uponinflation of the balloon in vivo, between 1% and 10% of the active agentto artery upon inflation of the balloon in vivo, between 3% and 10% ofthe active agent to artery upon inflation of the balloon in vivo, andbetween 1% and 5% of the active agent to artery upon inflation of theballoon in vivo.

In some embodiments, at least one of: at most 1% of coating is removedfrom the balloon due to tracking of the coated balloon to a treatmentsite, at most 5% of coating is removed from the balloon due to trackingof the coated balloon to the treatment site, at most 10% of coating isremoved from the balloon due to tracking of the coated balloon to thetreatment site, at most 15% of coating is removed from the balloon dueto tracking of the coated balloon to the treatment site, at most 20% ofcoating is removed from the balloon due to tracking of the coatedballoon to the treatment site, at most 25% of coating is removed fromthe balloon due to tracking of the coated balloon to the treatment site,and at most 30% of coating is removed from the balloon due to trackingof the coated balloon to the treatment site.

Provided herein is a device made according to any of the methodsprovided herein, and having features as described therein.

Example 9 Sirolimus Coated Balloon Animal (Rabbit) Study

Formulations 3, 19, 20, 21, 22, 23 were coated on balloons and theballoons were inflated in rabbit iliac arteries, and the arteries werestudied at 5 minutes, 72 hours and 14 days after inflation. Theobjective was to assess if Sirolimus from a drug coated balloon havingFormulations 3, 19, 20, 21, 22, or 23 coated thereon is retained inrabbit iliac arteries up to 72 hours and 14 days. The Formulation,coating composition, amount of sirolimus coated per balloon (inmicrograms), the sample size (n), and the coating appearance on theballoon is noted in Table 23. The study outline is noted in Table 24.

TABLE 23 Coating Formulation Coating Composition* Sirolimus/Balloon(μg)** Appearance F3 Sirolimus (1.5 μm), PLGA, 114.49 ± 25.18 (n = 18)Translucent, Very (Lot 3) Polyarginine 70 kDa Thick F19 Sirolimus (1.5μm), Polyarginine 5-15 kDa 138.99 ± 19.33 (n = 8)  Transparent, (Lot 1)Speckled F20 Sirolimus (1.5 μm), 25% PLGA, 223.36 ± 80.21 (n = 15)Opaque, Extremely (Lot 1) Polyarginine 5-15 kDa Thick F21 Sirolimus (1.5μm), Pullulan 200 kDa, 118.29 ± 27.23 (n = 15) Transparent, Thick,(Lot 1) Polyarginine 5-15 kDa Speckled F22 Sirolimus (1.5 μm),Ultravist, 85.19 ± 13.20 (n = 6) Tranparent, Light, (Lot 1) Polyarginine5-15 kDa Speckled F23 Sirolimus (1.5 μm), 25% PLGA, 143.97 ± 33.58 (n =6)  Translucent, Thick (Lot 1) Pullulan 200 kDa, Polyarginine 5-15 kDa*Sirolimus:Polyarginine ratio is 10:1 for all formulations.**Sirolimus/Balloon based on UV-Vis before pleating/folding andsterilization of balloons

TABLE 24 Micell DCB Treated Vessels Per Formulation Animals Animal BloodPK Necropsy Time Points Formulation 3 3 per time 2 balloon denuded 2 5Minutes, 3 Days, 14 Formulation 19 point iliac arteries treated(baseline/before Days (±5%) Formulation 20 with Micell DCB via necropsy)3 days (±5%) Formulation 21 one 60 second Formulation 22 inflationFormulation 23 Totals 30 Animals 60 Vessels 60 Bloods 5 min., 3 and 14Days (±5%) Deployed balloons, blood samples and denuded iliac arteriesanalyzed for Sirolimus levels. * Day 14 blood samples will be sent foranalysis only if drug detected in Day 3 blood samples. ** Day 14 animalsmay be sacrificed at a later time point based on arterial drug levels atDay 3.

As a result of the studies, it was found that Formulations 3 and 20 mostretained in arteries at 3 days. Remaining formulations did not providehigh levels of arterial retention. The 5 Minute Retention results showedthat F19 (no PLGA) retained ˜2 times more compared to F3 (w/PLGA). The 3Day Retention results showed that F3 and F20 were within the same levelof retention (˜4 ng/mg). There was retention variability in allformulations. In Whole Blood results showed that Sirolimus blood levelswere below 1 ng/ml by 3 days. Drug released from balloons results showedthat 70% to 97% Sirolimus was released depending on formulation.

Arterial sirolimus retention as a concentration in ng/mg, or as a totalsirolimus per artery in micrograms is shown in Table 25. Whole bloodsirolimus concentration in ng/mL, and estimated total sirolimus in theblood in micrograms is shown in Table 26. The quantitation limit forwhole blood sirolimus detection was 0.1 ng/mL. The balloon sirolimuslevels (tested on the balloon after deployment) and a calculated percentof sirolimus released or lost is provided in Table 27. The calculationof percent of sirolimus released or lost was based on batch average ofsirolimus on the balloon for each formulation, respectively.

TABLE 25 Arterial Sirolimus Total Sirolimus per Formulation Conc.(ng/mg) Artery (μg) F3: 5 Minutes 47.6 ± 30.1 (n = 6)   1.2 ± 0.8 (n =6) Sirolimus (1.5 μm), PLGA, Polyarginine 70 kDa F19: 5 Minutes 88.1 ±97.6 (n = 6)   2.5 ± 3.1 (n = 6) Sirolimus (1.5 μm), Polyarginine 5-15kDa F3: 3 Days  4.6 ± 5.1 (n = 6) 0.103 ± 0.117 (n = 6) Sirolimus (1.5μm), PLGA, Polyarginine 70 kDa F19: 3 Days 0.30 ± 0.26 (n = 6) 0.008 ±0.007 (n = 6) Sirolimus (1.5 μm), Polyarginine 5-15 kDa F20: 3 Days  3.8± 5.1 (n = 6) 0.089 ± 0.119 (n = 6) Sirolimus (1.5 μm), 25% PLGA,Polyarginine 5-15 kDa F21: 3 Days 0.11 ± 0.05 (n = 6) 0.003 ± 0.002 (n =6) Sirolimus (1.5 μm), Pullulan 200 kDa, Polyarginine 5-15 kDa F22: 3Days 0.34 ± 0.17 (n = 6) 0.008 ± 0.004 (n = 6) Sirolimus (1.5 μm),Ultravist, Polyarginine 5-15 kDa F23: 3 Days  1.2 ± 1.9 (n = 6) 0.028 ±0.040 (n = 6) Sirolimus (1.5 μm), 25% PLGA, Pullulan 200 kDa,Polyarginine 5-15 kDa

TABLE 26 Sirolimus Conc. in Est. Total Sirolimus Formulation: Time PointWhole Blood (ng/mL) in Blood (μg)* F3: 5 Minutes- Sirolimus 6.02 ± 1.43(n = 4) 1.49 ± 0.39 (n = 4) (1.5 μm), PLGA, Polyarginine 70 kDa F19: 5Minutes- 25.47 ± 10.08 (n = 3)  6.12 ± 2.43 (n = 3) Sirolimus (1.5 μm),Polyarginine 5-15 kDa F3: 3 Days- Sirolimus 0.38 ± 0.26 (n = 3) 0.09 ±0.06 (n = 3) (1.5 μm), PLGA, Polyarginine 70 kDa F19: 3 Days- Sirolimus0.34 ± 0.08 (n = 3) 0.08 ± 0.02 (n = 3) (1.5 μm), Polyarginine 5-15 kDaF20: 3 Days- Sirolimus 0.66 ± 0.26 (n = 3) 0.15 ± 0.06 (n = 3) (1.5 μm),25% PLGA, Polyarginine 5-15 kDa F21: 3 Days- Sirolimus 0.39 ± 0.02 (n =3) 0.09 ± 0.01 (n = 3) (1.5 μm), Pullulan 200 kDa Polyarginine 5-15 kDaF22: 3 Days- Sirolimus 0.23 ± 0.05 (n = 3) 0.05 ± 0.02 (n = 3) (1.5 μm),Ultravist, Polyarginine 5-15 kDa F23: 3 Days- Sirolimus 0.68 ± 0.13 (n =3) 0.15 ± 0.02 (n = 3) (1.5 μm), 25% PLGA, Pullulan 200 kDa,Polyarginine 5-15 kDa *Based on 56 mL Blood per kg

TABLE 27 Sirolimus Conc. on Balloon % Sirolimus Formulation postDeployment (ug) Released/Lost* F3 - Sirolimus (1.5 μm),  36.5 ± 7.9 (n =20)  69.7 ± 7.7% (n = 20) PLGA, Polyarginine 70 kDa F19 - Sirolimus (1.5μm),  6.9 ± 2.1 (n = 18)  95.0 ± 1.5% (n = 18) Polyarginine 5-15 kDaF20 - Sirolimus (1.5 μm), 27.9 ± 8.6 (n = 6) 87.4 ± 3.4% (n = 6) 25%PLGA, Polyarginine 5-15 kDa F21 - Sirolimus (1.5 μm),  3.9 ± 1.5 (n = 6)96.8 ± 1.2% (n = 6) Pullulan 200 kDa, Polyarginine 5-15 kDa F22 -Sirolimus (1.5 μm),  5.1 ± 0.8 (n = 6) 93.9 ± 0.9% (n = 6) Ultravist,Polyarginine 5-15 kDa F23 - Sirolimus (1.5 μm), 21.0 ± 6.0 (n = 6) 85.3± 3.6% (n = 6) 25% PLGA, Pullulan 200 kDa, Polyarginine 5-15 kDa *Basedon Balloon Batch Averages of Sirolimus

Multiple lots of Formulation 3 were produced to evaluation variabilityand effects generally of the sirolimus size (e.g. sirolimus having anaverage size of 2.5 microns versus sirolimus having an average size of1.5 microns). The results are presented in Table 28, Table 29, and Table30. Concentrations in Table 28 were normalized using a normalized arteryweight of 0.025 grams. The calculation of percent of sirolimus releasedor lost for Table 29 was based on batch average of sirolimus on theballoon for each formulation, respectively. The quantitation limit forwhole blood sirolimus detection was 0.1 ng/mL (for Table 30).

TABLE 28 5 minutes 24 hours 72 hours Sirolimus Sirolimus SirolimusConcentration Concentration Concentration Formulation Composition(ng/mg) (ng/mg) (ng/mg) F3 (LOT 1) - (PLGA, Sirolimus 119.2 ± 57.6 (n =6)  32.9 ± 18.0 (n = 8) 8.1 ± 5.7 (n = 6) 2.5 μm, Polyarginine 70 kDa)F3 (LOT 2) - (PLGA, Sirolimus 38.6 ± 16.3 (n = 2) 48.5 ± 63.7 (n = 2)41.1 (n = 1) 1.5 μm, Polyarginine 70 kDa) F3 (LOT 3) - (PLGA, Sirolimus47.6 ± 31.4 (n = 6) N/A 4.1 ± 4.7 (n = 6) 1.5 μm, Polyarginine 70 kDa)

TABLE 29 Sirolimus on Balloon Before Deployment Sirolimus on Balloon %Sirolimus Formulation Composition (ug) After Deployment (ug)Released/Lost* F3 (LOT 1) - (PLGA, Sirolimus 89.5 ± 19.6 (n = 9) 27.6 ±9.1 (n = 20) 68.4 ± 15.4% (n = 20) 2.5 μm, Polyarginine 70 kDa) F3 (LOT2) - (PLGA, Sirolimus 128.7 ± 26.9 (n = 42) 56.8 ± 15.6 (n = 6)  59.0 ±8.6% (n = 6) 1.5 μm, Polyarginine 70 kDa) F3 (LOT 3) - (PLGA, Sirolimus114.5 ± 25.2 (n = 18) 36.5 ± 7.9 (n = 20)  69.7 ± 7.7% (n = 20) 1.5 μm,Polyarginine 70 kDa) *Based on Balloon Batch Averages of Sirolimus

TABLE 30 Sirolimus Concentration in Whole Blood (ng/mL) FormulationComposition 5 minutes 24 hours 72 hours F3 (LOT 1) - (PLGA, Sirolimus7.7 ± 3.7 (n = 3) 0.8 ± 0.7 (n = 4) BQL (n = 3) 2.5 μm, Polyarginine 70kDa) F3 (LOT 2) - (PLGA, Sirolimus 5.5 (n = 1) BQL (n = 1) BQL (n = 1)1.5 μm, Polyarginine 70 kDa) F3 (LOT 3) - (PLGA, Sirolimus 6.0 ± 1.4 (n= 4) N/A 0.4 ± 0.3 (n = 3) 1.5 μm, Polyarginine 70 kDa)

Example 10 Coating of Rapamycin with PLGA Through Spray-Drying

In this example, rapamycin is coated with PLGA through a spray-dryingprocess. A mixture of 75 (w/w) % PLGA and 25 (w/w) % rapamycin isdissolved in THF to form a solution. Other polar aprotic solvent, suchas acetonitrile, or mixtures of polar aprotic solvents, can also be usedto form the solution. The solution is discharged from a spray nozzle andthe solvent is evaporated in a drying chamber to form thePLGA-encapsulate rapamycin particles, which are collected via continuousdischarge from the drying chamber to minimize thermal degradation. Inanother example, a slurry of rapamycin, PLGA, and water are spray driedto form the PLGA-encapsulated rapamycin particles.

The particle size of rapamycin can be controlled by adjusting sprayingparameters (e.g. pressure, temperature) and nozzle configurations (e.g.size, swirl chamber, rotory disk). In this example, the sprayingparameters and nozzle configuration are adjusted to produce rapamycinparticles having an average particle size of from 5 to 150 nm, and morepreferably from 10 to 100 nm. In other examples, the spraying parametersand nozzle configuration are adjusted to produce rapamycin particleshaving an average particle size of from 1 to 10 microns, and morepreferably from 1 to 5 microns.

Example 11 Coating of Rapamycin with PLGA Through Fluid Bed Coating

In this example, rapamycin particles (preferably crystallined, e.g.crystallinity of 25% to 95%) are micronized and suspended on a bed ofair, wherein a PLGA solution (e.g. 10-50 wt % in THF) is sprayed on thesuspended rapamycin particles. Other polar aprotic solvent may also beused. The particles are then transported to a drying chamber, where thesolvent are evaporated to form the PLGA-encapsulated rapamycinparticles. If needed, the encapsulated particles are re-suspended,sprayed with the PLGA solution, and dried until the coating thickness ofthe PLGA-encapsulated rapamycin particles reaches the desired level,e.g. 2 to 20 micron or about 10 microns.

Example 12 Coating of Rapamycin with PLGA Through Pan Coating

In this example, particles of PLGA, such as PLGA pellets, are added torapamycin particles in a tumbling vessel to form the PLGA-encapsulatedrapamycin particles. For example, PLGA may be ground, such as throughball mill, jet mill, or cryogenic grinding, to appropriate particle size(e.g. about 30 microns). The particle size and PLGA layer thickness ofthe encapsulated rapamycin can be controlled by the feeding rate of thePLGA pellets. In this example, the PLGA pellets are fed into thetumbling vessel at a rate of from 100 to 1000 μg per minute, preferablyfrom 300 to 500 μg per minute.

While Examples 10, 11, and 12 provide mechanical or physical method forencapsulation of the rapamycin in the PLGA, they should not beinterpreted as limiting the scope of the present disclosure. Chemicalmethods of encapsulation, such as core-shell emulsion preparationcomplex coacervation or in situ polymerization, can also be used to formthe encapsulated rapamycin.

Much of the description herein is provided with reference to a balloonand a treatment site that is an artery or blood vessel for ease ofdescription and brevity. Nevertheless, the methods, descriptions,devices, and coatings described herein apply to alternative devices andtreatment locations.

Unless otherwise stated, use of the term “about” in this description canmean variations of 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%,40%, and/or 50%, depending on the particular embodiment. Where theelement being described is itself expressed as a percent, the variationsare not meant to be percents of percents, rather they are variations asan absolute percent—i.e. an element that is expressed as “about 5%” maybe actually 5%+/−1%, or from 4% to 6%, depending on the embodiment. Onlythe variations that would be rational to one of ordinary skill in theart are contemplated herein. For example, where the element itself isexpressed as a small percent, and a person of ordinary skill would knowthat the element is not rational to go below 0, the variationscontemplated would not go below zero (i.e. about 5% could mean 5%+/−5%or 0-10%, but not 5%+/−10% or −5% to 15%, where this is not reasonableto one of skill in the art for the element being described).

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. While embodiments of the presentinvention have been indicated and described herein, it will be obviousto those skilled in the art that such embodiments are provided by way ofexample only. Numerous variations, changes, and substitutions will nowoccur to those skilled in the art without departing from the invention.It should be understood that various alternatives to the embodiments ofthe invention described herein may be employed in practicing theinvention. It is intended that the following claims define the scope ofthe invention and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

Example 13 Coating of Rapamycin with PLGA Through SingleEmulsion/Evaporation with Centrifuge

In this example, rapamycin is coated with PLGA through a singleemulsion/evaporation technique using a centrifuge to filter theemulsion. 200 mg poly(lactic-co-glycolic)acid (RG504H 0 viscosity0.45-0.6) was dissolved in 4 ml dichloromethane (oil phase). One hundredμl of a stock solution of rapamycin in Dimethyl Sulfoxide (10 mg/ml) wasdissolved in the oil phase, which was then homogenized at 10100 rpm for1 min in a 2% PVA (MW˜25,000, 98% hydrolyzed) solution, using ahomogenizer. This emulsion was immediately poured into 90 ml of a 1% PVAsolution, and dichloromethane was allowed to evaporate. After 3 hours,the particles were centrifuged (1500 g, 10 min, 4° C.) and washed fourtimes in deionized water. Microparticles were then re-suspended in 5 mlof deionized water, frozen on dry ice and lyophilized. Fluorescentlylabeled rapamycin-microparticles were prepared by adding 100 μl of 2mg/ml Alexa Fluor 647 carboxylic acid, succinimidyl ester to the oilphase along with the rapamycin and following the same protocol as above.

Example 14 Coating of Rapamycin with PLGA Through SingleEmulsion/Evaporation with Filter Paper

In this example, rapamycin is coated with PLGA through a singleemulsion/evaporation technique using filter paper to filter theemulsion. Five to 10 grams of PVA (Polyscience Inc, MW˜25,000, 98%hydrolyzed) was dissolved in warmed HPLC grade water to create 1% and 2%PVA solutions. Approximately 400 mg of 50:50 PolyDL-lactide-co-glycolide (Ester terminated, IV 0.55-0.75, DurectCorporation, Pelham, Ala.) was added to a 50 ml centrifuge tube anddissolved in 8 ml of Dichloromethane (oil phase). Approximately 10 mg ofrapamycin was added to 1 mL Dimethylsulfoxide and swirled until whiteparticles were no longer visible. 200 μl of the stock rapamycin solutionwas added to the oil phase. This solution was then poured into ˜100 mlof 2% PVA and homogenized for 1 min at ˜17,500 rpm. The emulsion wasthen poured into 180 ml of 1% PVA and left uncovered overnight to allowthe dichloromethane to evaporate. A frit funnel was lined with two size3 Whatman filter paper pieces (pre-wetted with HPLC grade water) priorto filtering the solution. The solution was poured through the filterpaper, leaving the particles on the filter paper. The particles werere-suspended by submerging the filter paper in 10 ml of water. Theliquid was transferred to a 100 ml round bottom flask which was frozenon dry ice and then lyophilized.

Referring now to FIG. 5, the encapsulated microparticles prepared inthis Example were examined for size and shape using a Hitachi ModelS-4700 scanning electron microscope (SEM). The SEM image shows that theencapsulated rapamycin particles prepared in this Example are generallysmooth and spherical. For example, at least 50%, 60%, 70%, 80%, or 90%of the particles have a generally spherical shape. FIG. 5 also shows ageneral particle size range of from about 0.5 μm to about 10 μm. Forexample, at least 50%, 60%, 70%, 80%, or 90% of the particles have asize range of about 0.5 μm to about 10 μm. The particles prepare in thisExample have an average particle size of from about 0.5 μm to about 10μm, from about 1 μm to about 10 μm, from about 1 μm to about 8 μm, fromabout 1 μm to about 7 μm, from about 1 μm to about 6 μm, from about 1 μmto about 5 μm, or from about 2 μm to about 4 μm. The presence ofrapamycin inside the microparticles was confirmed by UV-VIS spectroscopy(Perkin-Elmer Lambda 25 UV-Vis Spectrophotometer).

Example 15 Crystalline Rapamycin Encapsulation

Five to 10 g of PVA (MW 25,000, 98% hydrolyzed) was dissolved in warmedHPLC grade water to create 1% and 2% PVA solutions. Approximately 200 mgof 50:50 Poly DL-lactide-co-glycolide (Ester terminated, IV 0.55-0.75)was added to a 50 ml centrifuge tube and dissolved in 4 ml ofdichloromethane (oil phase). Approximately 50 ml of 1% PVA was added tothe oil phase and homogenized for 2 mins at ˜17,500 rpm. The emulsionwas left uncovered over night to allow the dichloromethane to evaporate.Approximately 1 mg of rapamycin was homogenized in 20 ml of 2% PVA fortwo minutes at ˜17,500 rpm. The rapamycin mixture was then added to thepolymer emulsion and homogenized for two minutes at ˜17,500 rpm. A fritfunnel was lined with two size 3 Whatman filter paper pieces (pre-wettedwith HPLC grade water) prior to filtering the solution. The solution waspoured through the filter paper, leaving the particles on the filterpaper. The particles were re-suspended by submerging the filter paper in10 ml of water. The liquid was transferred to a 100 ml round bottomflask which was frozen on dry ice then lyophilized.

Referring now to FIG. 6, the particles prepared in this Example wereexamined for size and shape using a Hitachi Model S-4700 scanningelectron microscope (SEM). The SEM image shows that the encapsulatedrapamycin particles prepared in this Example are generally smooth andspherical. For example, at least 50%, 60%, 70%, 80%, or 90% of theparticles have a generally spherical shape. FIG. 6 also shows a generalparticle size range of from about 1 μm to about 50 μm. For example, atleast 50%, 60%, 70%, 80%, or 90% of the particles have a size range ofabout 1 μm to about 50 μm. The particles prepare in this Example have anaverage particle size of from about 1 μm to about 50 μm, from about 1 μmto about 40 μm, from about 5 μm to about 40 μm, from about 5 μm to about35 μm, from about 5 μm to about 30 μm, from about 10 μm to about 30 μm,or from about 10 μm to about 20 μm. The presence of Rapamycin inside themicroparticles was confirmed by UV-VIS spectroscopy (Perkin-Elmer Lambda25 UV-Vis Spectrophotometer).

Example 16 Encapsulated Microparticle Characterization

Encapsulated microparticles are sized and counted using volume impedancemeasurements on a Beckman Coulter Counter. Average size was determinedby counting at least 10,000 particles. Microparticle surface morphologyand shape were examined using a scanning electronic microscope. Thesurface charge of the microparticles was determined by zeta potentialmeasurements.

SEM images of the particles show smooth surface morphology and confirmthe size obtained from the volume impedance measurements. The sizedistribution observed in SEM images is characteristic of themicroparticle encapsulation process described herein.

Example 17 Encapsulation Efficiency Characterization

Five mg of encapsulated rapamycin microparticles was dissolved in 1 mlof acetronitrile (HPLC grade), sonicated for 5 minutes and left under aconstant vortex for 30 min. The amount of rapamycin was then determinedby measuring absorbance of the solution at 278 nm using a UV-equippedplate reader. Encapsulation efficiency was calculated as the ratio ofrapamycin present inside particles to the amount of rapamycin that wasinitially added.

1. A medical device comprising: a balloon; and a coating on at least aportion of the balloon, wherein the coating comprises particles of apharmaceutical agent, and wherein each particle of the pharmaceuticalagent is at least partially encapsulated in a polymer material.
 2. Themedical device of claim 1, wherein at least 50% of the surface area ofthe pharmaceutical agent is encapsulated in the polymer material.
 3. Themedical device of claim 1, wherein at least 75% of the surface area ofthe pharmaceutical agent is encapsulated in the polymer material.
 4. Themedical device of claim 1, wherein at least 90% of the surface area ofthe pharmaceutical agent is encapsulated in the polymer material.
 5. Themedical device of claim 1, wherein at least 95% of the surface area ofthe pharmaceutical agent is encapsulated in the polymer material.
 6. Themedical device of claim 1, wherein the polymer layer has an averagethickness of from 2 microns to 20 microns.
 7. The medical device ofclaim 6, wherein the polymer layer has an average thickness of from 5microns to 15 microns.
 8. The medical device of claim 7, wherein thepolymer layer has an average thickness of about 10 microns.
 9. Themedical device of claim 1, wherein the pharmaceutical agent has acrystallinity of at least 5%.
 10. The medical device of claim 1, whereinthe pharmaceutical agent has a crystallinity of at least 20%.
 11. Themedical device of claim 1, wherein the pharmaceutical agent has acrystallinity of from 25% to 95%.
 12. The medical device of claim 1,wherein an average particle size of the encapsulated pharmaceuticalagent is from 5 nm to 150 nm.
 13. The medical device of claim 12,wherein an average particle size of the encapsulated pharmaceuticalagent is from 10 nm to 100 nm.
 14. The medical device of claim 1,wherein an average particle size of the encapsulated pharmaceuticalagent is from 1 micron to 50 micron.
 15. The medical device of claim 14,wherein an average particle size of the encapsulated pharmaceuticalagent is from 1 micron to 10 micron.
 16. The medical device of claim 1,wherein a weight ratio between the pharmaceutical agent and the polymermaterial is from 1:99 to 70:30.
 17. The medical device of claim 1,wherein a weight ratio between the pharmaceutical agent and the polymermaterial is from 25:75 to 40:60.
 18. The medical device of claim 1,wherein a weight ratio of the pharmaceutical agent and the polymermaterial is from 40:60 to 60:40.
 19. The medical device of claim 1,wherein the pharmaceutical agent is at least partially encapsulated inthe polymer material by spray-drying a mixture of the pharmaceuticalagent, the polymer material, and a solvent.
 20. The medical device ofclaim 19, wherein the mixture is a solution and the solvent is a polaraprotic solvent.
 21. The medical device of claim 20, wherein the polaraprotic solvent is selected from tetrahydrofuran, acetonitrile, andmixtures thereof.
 22. The medical device of claim 19, wherein themixture is a slurry and the solvent is water.
 23. The medical device ofclaim 1, wherein the pharmaceutical agent is at least partiallyencapsulated in the polymer material by spraying and drying a solutionof the polymer material on the particles of the pharmaceutical agent.24. The medical device of claim 23, wherein the solution comprises thepolymer material and a polar aprotic solvent.
 25. The medical device ofclaim 24, wherein the polar aprotic solvent is selected fromtetrahydrofuran, acetonitrile, and mixtures thereof.
 26. The medicaldevice of claim 1, wherein the pharmaceutical agent is at leastpartially encapsulated in the polymer material by adding particles ofthe polymer material to the pharmaceutical agent in a tumbling vessel.27. The medical device of claim 26, wherein the particles of the polymermaterial have an average particle size of from 10 microns to 100microns.
 28. The medical device of claim 26, wherein the particles ofthe polymer material are added at a rate of from 100 μg to 1000 μg perminute.
 29. The medical device of claim 28, wherein the particles of thepolymer material are added at a rate of from 300 μg to 500 μg perminute.
 30. The medical device of claim 1 wherein the pharmaceuticalagent is at least partially encapsulated in the polymer material byforming an emulsion-based mixture comprising the pharmaceutical agentand the polymer material, and separating the polymer-encapsulatedpharmaceutical agent from the emulsion-based mixture.
 31. The medicaldevice of claim 30, wherein the polymer material is a mixture of PVA andPLGA.
 32. The medical device of claim 31, wherein the PVA has an averagemolecular weight of from about 20,000 to about 30,000.
 33. The medicaldevice of claim 31, wherein the PLGA has a weight ratio from about 40:60to about 60:40 lactic acid:glycolic acid.
 34. The medical device ofclaim 30, wherein the pharmaceutical agent is amorphous.
 35. The medicaldevice of claim 34, wherein the pharmaceutical agent is at leastpartially encapsulated in the polymer material by forming theemulsion-based mixture comprising the pharmaceutical agent and thepolymer material, evaporating a portion of the emulsion-based mixture,and filtering the remaining emulsion-based mixture.
 36. The medicaldevice of claim 35, wherein the encapsulated pharmaceutical agent isresuspended and lyophilized.
 37. The medical device of claim 35, whereinthe emulsion-based mixture is formed by combining a first polymersolution, a second polymer solution, a third polymer solution, and apharmaceutical agent solution.
 38. The medical device of claim 37,wherein the first and third polymer solutions comprise a first polymerand water.
 39. The medical device of claim 38, wherein the first polymeris PVA.
 40. The medical device of claim 38, wherein the first polymersolution has a polymer concentration of from about 1% to about 5%. 41.The medical device of claim 38, wherein the third polymer solution has apolymer concentration of from about 0.5% to about 2%.
 42. The medicaldevice of claim 37, wherein the second polymer solution comprises asecond polymer and an organic solvent.
 43. The medical device of claim42, wherein the second polymer is PLGA.
 44. The medical device of claim42, wherein the organic solvent is dichloromethane.
 45. The medicaldevice of claim 37, wherein the pharmaceutical agent solution comprisesthe pharmaceutical agent and a polar aprotic solvent.
 46. The medicaldevice of claim 45, wherein the polar aprotic solvent isdimethylsulfoxide.
 47. The medical device of claim 37, wherein theemulsion-based mixture is formed by mixing the pharmaceutical agentsolution and the second polymer solution, adding the first polymersolution to the mixture, homogenizing the mixture, and adding the thirdpolymer solution.
 48. The medical device of claim 30, wherein thepharmaceutical agent is crystalline.
 49. The medical device of claim 48,wherein the pharmaceutical agent is at least partially encapsulated inthe polymer layer by forming the emulsion-based mixture comprising thepharmaceutical agent and the polymer material, evaporating a portion ofthe emulsion-based mixture, and filtering the remaining emulsion-basedmixture.
 50. The medical device of claim 48, wherein the encapsulatedpharmaceutical agent is resuspended and lyophilized.
 51. The medicaldevice of claim 50, wherein the emulsion-based mixture is formed bycombining a first polymer solution, a second polymer solution, a thirdpolymer solution, and the pharmaceutical agent.
 52. The medical deviceof claim 51, wherein the first polymer solution comprises a firstpolymer and an organic solvent.
 53. The medical device of claim 52,wherein the first polymer solution is combined with the second polymersolution and the organic solvent is allowed to evaporate.
 54. Themedical device of claim 52, wherein the first polymer is PLGA.
 55. Themedical device of claim 52, wherein the organic solvent isdichloromethane.
 56. The medical device of claim 51, wherein the secondand third polymer solutions comprise a second polymer and water.
 57. Themedical device of claim 56, wherein the second polymer is PVA.
 58. Themedical device of claim 56, wherein second polymer solution has apolymer concentration of from about 0.5% to about 2%.
 59. The medicaldevice of claim 56, wherein the third polymer solution has a polymerconcentration of from about 1% to about 5%.
 60. The medical device ofclaim 51, wherein the emulsion-based mixture is formed by mixing thefirst polymer solution and the second polymer solution to form anemulsion, mixing the pharmaceutical agent and the third polymer solutionto form a suspension, and combining the emulsion and suspension.
 61. Themedical device of claim 1, wherein the pharmaceutical agent is amacrolide immunosuppressant.
 62. The medical device of claim 61, whereinthe macrolide immunosuppressant is rapamycin or a derivative, a prodrug,a hydrate, an ester, a salt, a polymorph, a derivative or an analogthereof.
 63. The medical device of claim 61, wherein the macrolideimmunosuppressant is selected from the group consisting of rapamycin,40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin
 64. Themedical device of claim 1, wherein the pharmaceutical agent israpamycin.
 65. The medical device of claim 1, wherein the polymermaterial comprises a bioabsorbable polymer.
 66. The medical device ofclaim 65, wherein the bioabsorbable polymer is selected from the groupconsisting of polylactides (PLA); poly(lactide-co-glycolide) (PLGA);polyanhydrides; polyorthoesters; poly(N-(2-hydroxypropyl)methacrylamide); poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA);polyglycolide (PGA); poly(dioxanone) (PDO);poly(glycolide-co-trimethylene carbonate) (PGA-TMC);poly(l-lactide-co-glycolide) (PGA-LPLA); poly(dl-lactide-co-glycolide)(PGA-DLPLA); poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC),polyvinyl alcohol (PVA), polyarginine, and mixtures or co-polymersthereof.
 67. The medical device of claim 66, wherein the biodegradablepolymer is selected from the group consisting of PLGA, PVA,polyarginine, and mixtures thereof.
 68. The medical device of claim 1,wherein the polymer material comprises PLGA and PVA.
 69. The medicaldevice of claim 1, wherein the polymer material comprises PLGA.
 70. Themedical device of claim 69 wherein the PLGA comprises about 50:50 lacticacid:glycolic acid.
 71. The medical device of claim 1, wherein thepolymer material comprises a durable polymer.
 72. The medical device ofclaim 1, further comprising a binding agent deposited on an exteriorsurface of the encapsulated particles of the pharmaceutical agent. 73.The medical device of claim 72, wherein a weight ratio between thebinding agent and the polymer is from 1:99 to 25:75.
 74. The medicaldevice of claim 72, wherein a weight ratio between the binding agent andthe polymer is from 1:99 to 10:90.
 75. The medical device of claim 72,wherein the binding agent is deposited by spraying and drying a solutionof the binging agent on the encapsulated particles of the pharmaceuticalagent.
 76. The medical device of claim 75, wherein the solutioncomprises the binding agent and water.
 77. The medical device of claim72, wherein the binding agent comprises at least one of: polyarginine,polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethylcellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI(Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB(Dimethylditetradecylammonium bromide).
 78. The medical device of claim72, wherein the binding agent is polyarginine.
 79. The medical device ofclaim 78, wherein the polyarginine has an average molecular weight ofabout 70 kDa.
 80. The medical device of claim 78, wherein thepolyarginine has an average molecular weight of 5-15 kDa.
 81. Themedical device of claim 1 wherein the encapsulated particles of thepharmaceutical agent are deposited on the balloon using an eSTAT coatingprocess.
 82. The medical device of claim 1, wherein the device releasesat least 3% of the pharmaceutical agent upon inflation of the balloon.83. The medical device of claim 1 wherein the device releases at least5% or at least 10% of the pharmaceutical agent upon inflation of theballoon.
 84. The medical device of claim 1 wherein the device releasesat least about 2 ng/mg, at least about 3 ng/mg, at least about 5 ng/mg,at least about 10 ng/mg, at least about 20 ng/mg, at least about 30ng/mg, or at least about 40 ng/mg of the pharmaceutical agent 76 hoursafter inflation of the balloon.
 85. The medical device of claim 1,wherein the balloon is an invertable balloon having an abluminal side;wherein the coating is provided on the abluminal side of the invertableballoon.
 86. The medical device of claim 85, wherein the balloon isinverted within a catheter.
 87. The medical device of claim 86, whereinthe balloon is capable of being pushed out of the catheter using ballooninflation pressure or by moving the distal end of the balloon distallythrough the balloon, or a combination thereof.
 88. The medical device ofclaim 85, wherein the invertible balloon is inverted on an outside of acatheter.
 89. The medical device of claim 88, wherein a treatment lengthof the invertible balloon is controlled by partially un-inverting theinvertible balloon on the outside of the catheter.
 90. The medicaldevice of claim 88, further comprising a sheath provided over theinvertible balloon.
 91. The medical device of claim 90, wherein thesheath is retractable once the coated balloon reaches the treatmentsite, is positioned near the treatment site, is positioned at thetreatment site, is proximal to the treatment site, is distal to thetreatment site, or is within the treatment site.
 92. The medical deviceof claim 1, further comprising an occluder configured to block the flowof bodily fluids toward the balloon before the balloon is inflated. 93.The medical device of claim 92, wherein the occluder comprises a secondballoon.
 94. The medical device of claim 92, wherein the ballooncomprises first and second sections, the first section comprising theoccluder and the second section comprising the coating.
 95. The medicaldevice of claim 92, wherein the balloon comprises a distal node and aproximal node wherein the distal node comprises the coating and whereinthe proximal node comprises the occluder, or wherein the proximal nodecomprises the coating and wherein the distal node comprises theoccluder.
 96. The medical device of claim 92, wherein a distal portionof the balloon is coated and wherein a proximal portion of the balloonis not coated, and wherein the proximal portion of the balloon is theocclude, or wherein a proximal portion of the balloon is coated andwherein a distal portion of the balloon is not coated, and wherein thedistal portion of the balloon is the occluder.
 97. A method of releasinga pharmaceutical agent at a target site, comprising providing a devicecomprising a balloon, and a coating on at least a portion of theballoon, wherein the coating comprises particles of a pharmaceuticalagent, and wherein each particle of the pharmaceutical agent is at leastpartially encapsulated in a polymer material; positioning the device toallow the balloon to reach the target site; and inflating the balloon ofthe device, wherein at least some of the pharmaceutical agent isreleased to the target site upon inflating the balloon.
 98. The methodof claim 97, wherein the target site is a blood vessel.
 99. The methodof claim 97, wherein at least 3% of the pharmaceutical agent is releasedto the blood vessel upon inflation of the balloon.
 100. The method ofclaim 97, wherein at least 5% of the pharmaceutical agent is released tothe blood vessel upon inflation of the balloon.
 101. The method of claim97, wherein at least 10% of the pharmaceutical agent is released to theblood vessel upon inflation of the balloon.
 102. The method of claim 97,wherein the pharmaceutical agent is a macrolide immunosuppressant. 103.The method of claim 102, wherein the macrolide immunosuppressant israpamycin or a derivative, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative or an analog thereof.
 104. The method of claim102, wherein the macrolide immunosuppressant is selected from the groupconsisting of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin
 105. Themethod of claim 97, wherein the pharmaceutical agent is rapamycin. 106.The method of claim 97, wherein the polymer material comprises abiodegradable polymer.
 107. The method of claim 106 wherein thebioabsorbable polymer is selected from the group consisting ofpolylactides (PLA); poly(lactide-co-glycolide) (PLGA); polyanhydrides;polyorthoesters; poly(N-(2-hydroxypropyl) methacrylamide);poly(dl-lactide) (DLPLA); poly(l-lactide) (LPLA); polyglycolide (PGA);poly(dioxanone) (PDO); poly(glycolide-co-trimethylene carbonate)(PGA-TMC); poly(l-lactide-co-glycolide) (PGA-LPLA);poly(dl-lactide-co-glycolide) (PGA-DLPLA); poly(l-lactide-co-dl-lactide)(LPLA-DLPLA); poly(glycolide-co-trimethylene carbonate-co-dioxanone)(PDO-PGA-TMC), polyvinyl alcohol (PVA), and mixtures or co-polymersthereof.
 108. The method of claim 107, wherein the biodegradable polymeris selected from the group consisting of PLGA, PVA, polyarginine, andmixtures thereof.
 109. The method of claim 97, wherein the polymermaterial comprises PLGA and PVA.
 110. The method of claim 97, whereinthe polymer layer comprises PLGA.
 111. The method of claim 110, whereinthe PLGA comprises about 50:50 lactic acid:glycolic acid.
 112. Themethod of claim 110, wherein the polymer layer comprises a durablepolymer.
 113. The method of claim 97, wherein the device furthercomprises a binding agent deposited on an exterior surface of theencapsulated particles of the pharmaceutical agent.
 114. The method ofclaim 113, wherein the binding agents comprises at least one of:polyarginine, polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethylcellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI(Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB(Dimethylditetradecylammonium bromide).
 115. The method of claim 113,wherein the binding agent is polyarginine.
 116. The method of claim 97,wherein the encapsulated particles of the pharmaceutical agent aredeposited on the balloon using an eSTAT coating process.
 117. A methodof forming polymer-encapsulated crystalline rapamycin, the methodcomprising: forming the emulsion-based mixture comprising thepharmaceutical agent and the polymer material; evaporating a portion ofthe emulsion-based mixture, and filtering the remaining emulsion-basedmixture.
 118. The method claim 117, further comprising resuspending andlyophilizing the encapsulated pharmaceutical agent.
 119. The method ofclaim 117, wherein the emulsion-based mixture is formed by combining afirst polymer solution, a second polymer solution, a third polymersolution, and the pharmaceutical agent.
 120. The method of claim 119,wherein the first polymer solution comprises a first polymer and anorganic solvent.
 121. The method of claim 120, wherein the first polymersolution is combined with the second polymer solution and the organicsolvent is allowed to evaporate.
 122. The method of claim 121, whereinthe first polymer is PLGA.
 123. The method of claim 122, wherein theorganic solvent is dichloromethane.
 124. The method of claim 119,wherein the second and third polymer solutions comprise a second polymerand water.
 125. The method of claim 124, wherein the second polymer isPVA.
 126. The method of claim 125, wherein second polymer solution has apolymer concentration of from about 0.5% to about 2%.
 127. The method ofclaim 125, wherein the third polymer solution has a polymerconcentration of from about 1% to about 5%.
 128. The method of claim119, wherein the emulsion-based mixture is formed by mixing the firstpolymer solution and the second polymer solution to form an emulsion,mixing the pharmaceutical agent and the third polymer solution to form asuspension, and combining the emulsion and suspension.